Sphingosine kinase inhibitor amidoxime prodrugs

ABSTRACT

Sphingosine kinases are enzymes that catalyze the biosynthesis of sphingosine-1-phosphate. The invention provides prodrugs of compounds that are effective for inhibition of sphingosine kinase type 1, sphingosine kinase type 2, or both, according to formula (I) as described herein. Formula I compounds are useful in the treatment of a range of diseases wherein increasing the level of sphingosine-1-phosphate in blood is medically indicated. The invention also provides pharmaceutical compositions of Formula I compounds.

PRIORITY APPLICATION

This application claims priority to U.S. Provisional Application Ser.No. 62/315,193, filed Mar. 30, 2016, the disclosure of which isincorporated herein in its entirety by reference.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under GM106495 andGM104366 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND

Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokesa variety of cellular processes, including those that result in cellproliferation, cell morphology, tumor-cell invasion, endothelial cellchemotaxis, and angiogenesis. S1P mediates its effects on cellularbehavior through the S1P receptors, a family of five cell surface Gprotein coupled receptors called S1P1, S1P2, S1P3, S1P4, and S1P5, whichwere formerly known as EDG-1, -3, -5, -6, and -8, respectively. Inaddition to the S1P receptors, S1P also activates various lesswell-defined intracellular targets. The EDG receptors are G-proteincoupled receptors (GPCRs) and on stimulation propagate second messengersignals via activation of heterotrimeric G-protein alpha (G_(α))subunits and beta-gamma (G_(βγ)) dimers. Ultimately, this S1P-drivensignaling results in cell survival, increased cell migration and often,mitogenesis. The recent development of agonists targeting S1P receptorshas provided insight regarding the role of this signaling system inphysiologic homeostasis.

S1P is synthesized by the action of two enzymes, sphingosine kinasetypes 1 and 2 (SphK1, SphK2). These enzymes catalyze the transfer of aphosphate residue from adenosine triphosphate (ATP) to D-erythrosphingosine. SphK1 and SphK2 also catalyze the phosphorylation ofreduced sphingosine (D-erythro sphinganine) and hydroxylated sphinganine(D-ribo phytosphingosine) to yield sphinganine 1-phosphate (dihydroS1P)and phytosphingosine 1-phosphate.

One example of a non-S1P agonist is the phosphorylated form of theimmunomodulator, fingolimod (2-amino-2-[2-(4-octylphenyl) ethyl] propane1,3-diol), which is an agonist of four of the five S1P receptors.Enhancing S1P tone at S1P1 influences lymphocyte trafficking bydecreasing lymphocyte egress from secondary lymphoid tissues. Consistentwith the role of S1P1 agonists in preventing lymphocyte egress,antagonists of some S1P1 receptors cause leakage of the lung capillaryendothelium, which suggests that S1P may be involved in maintaining theintegrity of the endothelial barrier in some tissue beds.

Indeed, infection and tissue injury induce a cascade of biochemicalchanges that trigger reactions of the immune system, collectivelyreferred to as an inflammatory response. The evolution of this responseis based, at least in part, on enhancing vascular permeability andactivation of the vascular endothelium, which allows white blood cellsto efficiently circulate and migrate to the damaged site, therebyincreasing their chances to bind to and destroy any antigens. Thevascular endothelium is then thought to be activated or inflamed.Generally, inflammation is a welcomed immune response to a variety ofunexpected stimuli, and as such it exhibits rapid onset and shortduration (acute inflammation). Its persistent or uncontrolled activity(chronic inflammation) has, however, detrimental effects to the body andresults in the pathogenesis of several immune diseases, such as: septicshock, rheumatoid arthritis, inflammatory bowel diseases, acute lunginjury, pulmonary fibrosis, and congestive heart failure, for example.Furthermore, chronic inflammation resulting from persistent tissueinjury can lead to organ fibrosis, and eventually, organ failure, as isthe case in idiopathic pulmonary fibrosis, end-stage renal failure, andliver cirrhosis, for example.

During vascular injury and in inflammation thrombin is also releasedfrom the blood, and it activates thrombin receptors (PA s) expressed onendothelial surface. Thrombin and thrombin receptors regulate variousendothelial functions and play a role in the response of endothelialcells to vascular injury, including inducing cytoskeletal changesresulting in cell rounding. Contraction of endothelial cells leads toincreased permeability and compromises in the endothelial barrier. Incontrast to the edemagenic effects of thrombin, S1P may enhanceendothelial cell barrier properties.

S1P has also been shown to have a direct role in modulating severalimportant effects on cells that mediate immune functions. Platelets,monocytes and mast cells secrete S1P upon activation, promotinginflammatory cascades at the site of tissue damage. Activation of SphKis required for the signaling responses since the ability of TNF-α toinduce adhesion molecule expression via activation of Nuclear FactorKappa B (NFκB) is mimicked by S1P and is blocked by DMS. Similarly, S1Pmimics the ability of TNF-α to induce the expression of cyclooxygenase-2(COX-2) and the synthesis of prostaglandin E₂ (PGE₂), and knock-down ofSphK by RNA interference blocks these responses to TNF-α. S1P is also amediator of calcium influx during neutrophil activation by TNF-α andother stimuli, leading to the production of superoxide and other toxicradicals. Therefore, reducing the production of S1P within immune cellsand their target tissues may be an effective method to treat disordersarising from oxidative stress and abnormal inflammation. Examples ofsuch disorders include inflammatory bowel disease, arthritis,atherosclerosis, asthma, allergy, inflammatory kidney disease,circulatory shock, ischemia-reperfusion injury, post-surgical organfailure, organ transplantation, multiple sclerosis, chronic obstructivepulmonary disease, skin inflammation, periodontal disease, psoriasis andT cell-mediated diseases of immunity.

S1P also has several effects on cells that mediate immune functions. Forexample, platelets, monocytes, and mast cells secrete S1P uponactivation, promoting inflammatory cascades. It is believed that SphKactivation is required for the related signaling responses. In addition,deregulation of apoptosis in phagocytes can be an important component ofchronic inflammatory diseases. S1P has been found to protect neutrophilsand macrophages in response to inflammatory stresses, such as TNF-α.Additional information regarding the role of S1P and SphK in variousspecific inflammatory and/or autoimmune conditions can be found in U.S.Patent Application Publication No. 2008/0167352, the disclosure of whichis incorporated herein. Accordingly, inhibition of the enzymaticactivity of SphK (which can reduce levels of S1P) can prevent thehyperproliferation of immune cells that are important for inflammation.

S1P also has effects on vascular contractility, vascular tone, and bloodpressure control. For example, the non-S1P agonist, fingolimod producesmodest hypertension in patients (2-3 mmHg in 1-yr trial). In addition,it has been found that exogenous S1P elicits a marked Ca²⁺- and Rhokinase-dependent pulmonary vasoconstriction in hypertensive rat lungs.Furthermore, it has been found that S1P selectively and potentlyconstricts isolated cerebral arteries. Therefore, reducing S1P levelsmay be an effective method to treat disease or disorders arising fromhypertension. Examples of such diseases or disorders include chronickidney disease, pulmonary hypertension, pulmonary arterial hypertension,atherosclerosis, and stroke.

Given S1P's involvement in mediating disease pathologies associated withchanges in cellular proliferation, morphology, migration, andchemotaxis, sphingosine kinases are good targets for therapeuticapplications such as modulating fibrosis, tumor growth inhibition,angiogenesis, endothelial cell chemotaxis, and inflammatory andautoimmune diseases and disorders. For example, SphK1 and SphK2 haveroles in affecting cell survival and proliferation. These kinases arealso responsible for the equilibrium between the anti-apoptotic SU′ andits pro-apoptotic metabolic precursor sphingosine and its precursor,ceramide. Thus, SphK1 and SphK2 are important drug targets.

To date, only a small number of compounds includingDL-threo-dihydrosphingosine, N,N-dimethylsphingosine, and short-chainDL-erythro-sphingosine analogues, have been shown to inhibit sphingosinekinases. However, with a typical K_(I) value in excess of 10 μM, thesecompounds have relatively low potency. These compounds are also neithergenerally selective for either SphK1 or SphK2, nor are theymetabolically stable in vivo. Accordingly, these compounds are notideally suited for addressing questions concerning SphK mediated diseasestates.

Traditional methods of inhibiting kinases, including sphingosinekinases, have centered on targeting the ATP binding site of the kinase,a strategy that has enjoyed moderate success. However, such methodssuffer from lack of selectivity across a wide array of kinases.Additionally, the amino acid sequence of the ATP binding domain of SphK1and SphK2 is conserved across a number of diacylglycerol (DAG) kinasefamily members, rendering the traditional strategy problematic becauseit does not discriminate among kinases. By contrast, the inhibitors inthe present invention are competitive with sphingosine, not with ATP,and thus are not expected to inhibit other protein and diacylglycerolkinases.

Currently, there is a need for novel, potent, and selective agents thatinhibit the sphingosine substrate-binding domain of the sphingosinekinases (e.g., human SphK1 or SphK2, or both) that have enhancedpotency, selectivity, and bioavailability. In addition, there is a needin the art for identification, as well as the synthesis and use, of suchcompounds. The present invention satisfies these needs.

SUMMARY

One embodiment of the invention is a compound of formula (I):

wherein

-   -   X is phenyl, indolyl, or naphthyl;    -   R¹ and R² are independently selected from the group consisting        of H, OH, —(C₁-C₆)alkyl-OH, halo, NH₂, NOH, NHOH, and CN;        -   or R¹ and R², if bound to adjacent carbon atoms, in            combination with the existing carbon-carbon bond represent a            double bond between the adjacent carbon atoms;    -   R³ and R⁴ are independently selected from the group consisting        of H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₆)haloalkyl, CN, and        halo;    -   m=0 or 1;    -   W is CH₂, O or, NH;    -   V is selected from the group consisting of H, (C₁-C₁₀)alkyl,        (C₂-C₁₂)alkenyl, —(C₁-C₁₀)alkyl-(C₆-C₁₀)aryl,        —(C₂-C₁₂)alkenyl-(C₆-C₁₀)aryl,        —(C₁-C₁₀)alkyl-(C₆-C₁₀)aryl-(C₁-C₁₀)alkyl,        —(C₁-C₁₀)alkyl-(C₃-C₈)cycloalkyl, —(C₁-C₁₀)alkyl-heterocyclyl        containing from 1 to 3 ring heteroatoms selected from N, O, and        S;        -   wherein any aryl is optionally fused to (C₆-C₁₀)aryl,            (C₃-C₅)cycloalkyl, or heterocyclyl containing from 1 to 3            ring heteroatoms selected from N, O, and S        -   wherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, or            aryl is optionally substituted by 1-4 substituents            independently selected from the group consisting of F, Cl,            Br, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, (C₂-C₆)alkenyl,            (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl, and CN;    -   Y¹, Y², and Y³ are independently selected from the group        consisting of C, N, NH, O, and S;        or a pharmaceutically acceptable salt thereof.

The invention also provides, in various embodiments, a subset of formula(I) compounds according to formula (II)

wherein:

-   -   R¹ and R² are H, or when m=1, one of R¹ and R² can be OH;    -   R³ and R⁴ are each independently H, (C₁-C₄)alkyl, cyclopropyl,        (C₁-C₂)fluoroalkyl, cyano, or halo;    -   m=0 or 1;    -   each of Y¹, Y², and Y³ is independently selected from the group        consisting of C, N, NH, O, and S;    -   X is a phenyl, naphthyl, or indolyl;    -   W is O or CH₂;    -   V is (C₅-C₁₀)alkyl;        or a pharmaceutically acceptable salt thereof.

In some Formula II compounds, Y¹ and Y² are N and Y³ is O, X is phenyl,R¹ and R² are H, R³ is trifluoromethyl, R⁴ is H, and V is (C₈-C₉)alkyl.

In various embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of formula (I) and a pharmaceuticallyacceptable excipient.

In various embodiments, the invention provides a method of inhibiting asphingosine kinase, comprising contacting the sphingosine kinase with aneffective amount or concentration of a compound of formula (I) or aneffective amount of a pharmaceutical composition comprising a compoundof formula (I) in any of its embodiments. The sphingosine kinase can besphingosine kinase type 1 or sphingosine kinase type 2. The compound offormula (I) can be a selective inhibitor of one of sphingosine kinasestype 1 or type 2 relative to the other of sphingosine kinases type 1 ortype 2.

In various embodiments, as described in greater detail below, theinvention provides methods of treatment of various diseases in patientsafflicted therewith wherein inhibition of a sphingosine kinase, forinstance sphingosine kinase type 1 or type 2, is medically indicated, orwherein increasing blood plasma levels of sphingosine-1-phosphate ismedically indicated, or both.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B. Four C57Bl/6 mice were dosed by oral gavage with 20 mg/kgof Compound 6. At the indicated times, blood was drawn, whole preparedfor analysis, and the amount sphingosine 1-phosphate (S1P) wasquantified by LC-MS-MS (FIG. 1A). The rise in S1P is indicative ofinhibition of sphingosine kinase type 2 (SphK2). The amounts of Compound6 (checkered) and its reduced form (i.e. Compound 6A (solid black)) wasdetected by LC-MS-MS in the same blood samples (FIG. 1B).

DETAILED DESCRIPTION

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

The term “about” as used herein, when referring to a numerical value orrange, allows for a degree of variability in the value or range, forexample, within 10%, or within 5% of a stated value or of a stated limitof a range.

All percent compositions are given as weight-percentages, unlessotherwise stated.

As used herein, “individual” (as in the subject of the treatment) or“patient” means both mammals and non-mammals. Mammals include, forexample, humans; non-human primates, e.g. apes and monkeys; andnon-primates, e.g. dogs, cats, cattle, horses, sheep, and goats.Non-mammals include, for example, fish and birds.

The expression “effective amount”, when used to describe therapy to anindividual suffering from a disorder, refers to the quantity orconcentration of a compound of the invention that is effective toinhibit or otherwise act on a sphingosine kinase in the individual'stissues wherein a sphingosine kinase, such as sphingosine kinase type 1or sphingosine kinase type 2, is involved in the disorder, wherein suchinhibition or other action occurs to an extent sufficient to produce abeneficial therapeutic effect.

The expression “effective amount”, when used to describe induction ofneuromuscular blockade or reversal of that blockade refers to the amountof a compound of the invention that is effective to bring about thedesired effects in an individual being treated, which is adjusted basedon the knowledge and discretion of the attending physician and takesinto account significant medical factors.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder, or curing thedisease or disorder. Similarly, as used herein, an “effective amount” ora “therapeutically effective amount” of a compound of the inventionrefers to an amount of the compound that alleviates, in whole or inpart, symptoms associated with the disorder or condition, or halts orslows further progression or worsening of those symptoms, or prevents,or provides prophylaxis for, the disorder or condition. In particular, a“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result. A therapeutically effective amount is also one inwhich any toxic or detrimental effects of compounds of the invention areoutweighed by the therapeutically beneficial effects.

The following abbreviations are used: sphingosine kinase (“SphK”);sphingosine kinase type 1 (“SphK1”); sphingosine kinase type 2(“SphK2”); sphingosine (“Sph”); sphingosine 1-phosphate (“S1P”);sphinganine (“dhSph” or “H2Sph”); sphinganine 1-phosphate (“dhS1P” or“H2S1P”).

The term “affected cell” refers to a cell of a subject afflicted with adisease or disorder, which affected cell has an altered phenotyperelative to a subject not afflicted with a disease or disorder.

Cells or tissue are “affected” by a disease or disorder if the cells ortissue have an altered phenotype relative to the same cells or tissue ina subject not afflicted with a disease or disorder.

A disease or disorder is “alleviated” if the severity of a symptom ofthe disease or disorder, the frequency with which such a symptom isexperienced by a patient, or both, is reduced.

The terms “cell,” “cell line,” and “cell culture” may be usedinterchangeably.

A “control” cell, tissue, sample, or subject is a cell, tissue, sample,or subject of the same type as a test cell, tissue, sample, or subject.The control may, for example, be examined at precisely or nearly thesame time the test cell, tissue, sample, or subject is examined. Thecontrol may also, for example, be examined at a time distant from thetime at which the test cell, tissue, sample, or subject is examined, andthe results of the examination of the control may be recorded so thatthe recorded results may be compared with results obtained byexamination of a test cell, tissue, sample, or subject. The control mayalso be obtained from another source or similar source other than thetest group or a test subject, where the test sample is obtained from asubject suspected of having a disease or disorder for which the test isbeing performed.

A “test” cell, tissue, sample, or subject is one being examined ortreated.

A “pathoindicative” cell, tissue, or sample is one which, when present,is an indication that the animal in which the cell, tissue, or sample islocated (or from which the tissue is obtained) is afflicted with adisease or disorder. By way of example, the presence of one or morebreast cells in a lung tissue of an animal is an indication that theanimal is afflicted with metastatic breast cancer.

A tissue “normally comprises” a cell if one or more of the cell arepresent in the tissue in an animal not afflicted with a disease ordisorder.

The use of the word “detect” and its grammatical variants is meant torefer to measurement of the species without quantification, whereas useof the word “determine” or “measure” with their grammatical variants aremeant to refer to measurement of the species with quantification. Theterms “detect” and “identify” are used interchangeably herein.

A “detectable marker” or a “reporter molecule” is an atom or a moleculethat permits the specific detection of a compound having the marker inthe presence of similar compounds without a marker. Detectable markersor reporter molecules include, e.g., radioactive isotopes, antigenicdeterminants, enzymes, nucleic acids available for hybridization,chromophores, fluorophores, chemiluminescent molecules,electrochemically detectable molecules, and molecules that provide foraltered fluorescence-polarization or altered light-scattering.

The term “disease” or “disorder” or “malcondition” are usedinterchangeably, and are used to refer to diseases or conditions whereina sphingosine kinase, such as sphingosine kinase type 1 or sphingosinekinase type 2, plays a role in the biochemical mechanisms involved inthe disease or malcondition or symptom(s) thereof such that atherapeutically beneficial effect can be achieved by acting on thesphingosine kinase, e.g. with an effective amount or concentration of asynthetic ligand of formula (I) of the invention. “Acting on”sphingosine kinase, or “modulating” sphingosine kinase, can includebinding to sphingosine kinase and/or inhibiting the bioactivity ofsphingosine kinase and/or allosterically regulating the bioactivity ofsphingosine kinase in vivo. Thus, a “disease” is a state of health of ananimal wherein the animal cannot maintain homeostasis, and wherein ifthe disease is not ameliorated then the animal's health continues todeteriorate.

A “disorder” in an animal is a state of health in which the animal isable to maintain homeostasis, but in which the animal's state of healthis less favorable than it would be in the absence of the disorder. Leftuntreated, a disorder does not necessarily cause a further decrease inthe animal's state of health.

An “autoimmune disease” is a disease or disorder arising from anddirected against an individual's own tissues. Examples of autoimmunediseases or disorders include, but are not limited to arthritis(rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis,psoriatic arthritis), Caplan's Syndrome, Felty's Syndrome, psoriasis,dermatitis, Sjorgren's Syndrome, Still's Disease,polymyositis/dermatomyositis, toxic epidermal necrolysis, systemicscleroderma and sclerosis, responses associated with inflammatory boweldisease, Crohn's disease, ulcerative colitis, respiratory distresssyndrome, adult respiratory distress syndrome (ARDS), meningitis,encephalitis, uveitis, colitis, glomerulonephritis, allergic conditions,eczema, asthma, conditions involving infiltration of T cells and chronicinflammatory responses, atherosclerosis, autoimmune myocarditis,leukocyte adhesion deficiency, systemic lupus erythematosus (SLE),juvenile onset diabetes, multiple sclerosis, allergic encephalomyelitis,immune responses associated with acute and delayed hypersensitivitymediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis,granulomatosis including Wegener's granulomatosis, agranulocytosis,vasculitis (including ANCA), aplastic anemia, Diamond Blackfan anemia,immune hemolytic anemia including autoimmune hemolytic anemia (MBA),pernicious anemia, pure red cell aplasia (PRCA), Factor VIII deficiency,hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseasesinvolving leukocyte diapedesis, central nervous system (CNS)inflammatory disorders, multiple organ injury syndrome, mysatheniagravis, antigen-antibody complex mediated diseases, anti-glomerularbasement membrane disease, anti-phospholipid antibody syndrome, allergicneuritis, Bechet disease, Castleman's syndrome, Goodpasture's syndrome,Lambert-Eaton Myasthenic Syndrome, Reynaud's syndrome, Sjorgen'ssyndrome, Stevens-Johnson syndrome, solid organ transplant rejection,graft versus host disease (GVHD), pemphigoid bullous, pemphigus,autoimmune polyendocrinopathies, Reiter's disease, stiff-man syndrome,giant cell arteritis, immune complex nephritis, IgA nephropathy, IgMpolyneuropathies or IgM mediated neuropathy, idiopathic thrombocytopenicpurpura (ITP), thrombotic throbocytopenic purpura (TTP), autoimmunethrombocytopenia, autoimmune disease of the testis and ovary includingautoimmune orchitis and oophoritis, primary hypothyroidism; autoimmuneendocrine diseases including autoimmune thyroiditis, chronic thyroiditis(Hashimoto's Thyroiditis), subacute thyroiditis, idiopathichypothyroidism, Addison's disease, Grave's disease, autoimmunepolyglandular syndromes (or polyglandular endocrinopathy syndromes),Type I diabetes also referred to as insulin-dependent diabetes mellitus(IDDM) and Sheehan's syndrome; autoimmune hepatitis, lymphoidinterstitial pneumonitis (HIV), bronchiolitis obliterans(non-transplant) vs NSIP, Guillain-Barre' syndrome, large vesselvasculitis (including polymyalgia rheumatica and giant cell (Takayasu's)arteritis), medium vessel vasculitis (including Kawasaki's disease andpolyarteritis nodosa), ankylosing spondylitis, Berger's disease (IgAnephropathy), rapidly progressive glomerulonephritis, primary biliarycirrhosis, Celiac sprue (gluten enteropathy), cryoglobulinemia,amyotrophic lateral sclerosis (ALS), coronary artery disease etc.

An “inflammatory disease” may be any automimmune disease, as well asinclude, but not be limited to: ulcerative colitis, and Crohn's disease;cardiovascular diseases such as ischemic cardiac disease and heartfailure; cerebrovascular diseases; kidney diseases, includingglomerulonephritis, glomerular injury, nephrotic syndrome, interstitialnephritis, lupus nephritis, Goodpasture's disease, Wegener'sgranulomatosis, renal vasculitis, IgA nephropathy and idiopathicglomerular disease; diabetes; diabetes complications such asretinopathy, nephropathy, nerve disease, and coronary arterial disease;skin diseases, including allergic skin disease, psoriasis, atopicdermatitis, contact sensitivity and acne; obesity; nephritis; hepatitis;cancer; Alzheimer's disease; inflammatory diseases that are caused byinflammatory cytokines; skin diseases such as allergic skin diseases;chondrocalcinosis; gout; rheumatic fever and

Reiter's Disease.

The term “Immune cell(s)” include, but are not limited to, lymphocytes,(including CD4⁺ T cells, CD8⁺ T cells, Natural Killer T cells, and Bcells), mast cells, basophils, macrophaged, dendritic cells, monocytes,eosinophils, neutrophils, or any other cell type that functions withinthe immune system.

“Vascular permeability” refers to the capacity of small molecules (e.g.,ions, water, nutrients), large molecules (e.g., proteins and nucleicacids) or even whole cells (lymphocytes on their way to the site ofinflammation) to pass through a blood vessel wall. Diseases anddisorders characterized by undesirable vascular permeability include,for example, edema associated with brain tumors, ascites associated withmalignancies, Meigs' syndrome, lung inflammation, nepbrotic syndrome,pericardial effusion and pleural effusion.

A “functional” molecule is a molecule in a form in which it exhibits aproperty by which it is characterized. By way of example, a functionalenzyme is one that exhibits the characteristic catalytic activity bywhich the enzyme is characterized.

The term “inhibit” refers to the ability of a disclosed compound toreduce or impede a described function. Inhibition is by at least 10%,preferably by at least 25%, more preferably by at least 50%, even morepreferably by at least 75%, and most preferably, the function isinhibited by at least 95%.

The term “selective” refers to the ability of the disclosed compounds toinhibit one of the sphingosine kinase 1 or sphingosine kinase 2 (SphK1 &SphK2) enzymes and not the other enzyme. Preferably, the selectivecompound will have a K_(I) value for one enzyme that is less than, by atleast an order of magnitude (e.g., a ten-fold difference), the K_(I)value for the other enzyme or in inhibition of one of the SphK enzymesover the other enzyme.

By “chemically feasible” is meant a bonding arrangement or a compoundwhere the generally understood rules of organic structure are notviolated; for example a structure within a definition of a claim thatwould contain in certain situations, e.g., a pentavalent carbon atomthat would not exist in nature would be understood to not be within theclaim. The structures disclosed herein, in all of their embodiments areintended to include only “chemically feasible” structures, and anyrecited structures that are not chemically feasible, for example in astructure shown with variable atoms or groups, are not intended to bedisclosed or claimed herein.

When a substituent is specified to be an atom or atoms of specifiedidentity, “or a bond”, a configuration is referred to when thesubstituent is “a bond” that the groups that are immediately adjacent tothe specified substituent are directly connected to each other in achemically feasible bonding configuration.

All single enantiomer, diastereomeric, and racemic forms of a structureare intended, unless a particular stereochemistry or isomeric form isspecifically indicated. In several instances though an individualstereoisomer is described among specifically claimed compounds, thestereochemical designation does not imply that alternate isomeric formsare less preferred, undesired, or not claimed. Compounds used in thepresent invention can include enriched or resolved optical isomers atany or all asymmetric atoms as are apparent from the depictions, at anydegree of enrichment. Both racemic and diastereomeric mixtures, as wellas the individual optical isomers can be isolated or synthesized so asto be substantially free of their enantiomeric or diastereomericpartners, and these are all within the scope of the invention.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.The priority of substituents is ranked based on atomic weights, a higheratomic weight, as determined by the systematic procedure, having ahigher priority ranking. Once the priority ranking of the four groups isdetermined, the molecule is oriented so that the lowest ranking group ispointed away from the viewer. Then, if the descending rank order of theother groups proceeds clockwise, the molecule is designated as having an(R) absolute configuration, and if the descending rank of the othergroups proceeds counterclockwise, the molecule is designated as havingan (S) absolute configuration. In the example in the Scheme below, theCahn-Ingold-Prelog ranking is A>B>C>D. The lowest ranking atom, D isoriented away from the viewer. The solid wedge indicates that the atombonded thereby projects toward the viewer out of the plane of the paper,and a dashed wedge indicates that the atom bonded thereby projects awayfrom the viewer out of the plan of the paper, i.e., the plane “of thepaper” being defined by atoms A, C, and the chiral carbon atom for the(R) configuration shown below.

A carbon atom bearing the A-D atoms as shown above is known as a“chiral” carbon atom, and the position of such a carbon atom in amolecule is termed a “chiral center.” Compounds of the invention maycontain more than one chiral center, and the configuration at eachchiral center is described in the same fashion.

There are various conventions for depicting chiral structures usingsolid and dashed wedges. For example, for the (R) configuration shownabove, the following two depictions are equivalent:

The present invention is meant to encompass diastereomers as well astheir racemic and resolved, diastereomerically and enantiomerically pureforms and salts thereof. Diastereomeric pairs may be resolved by knownseparation techniques including normal and reverse phase chromatography,and crystallization.

“Isolated optical isomer” or “isolated enantiomer” means a compoundwhich has been substantially purified from the corresponding opticalisomer(s) of the same formula. Preferably, the isolated isomer is atleast about 80%, more preferably at least 90% enantiomerically pure,even more preferably at least 98% enantiomerically pure, most preferablyat least about 99% enantiomerically pure, by weight. By “enantiomericpurity” is meant the percent of the predominant enantiomer in anenantiomeric mixture of optical isomers of a compound. A pure singleenantiomer has an enantiomeric purity of 100%.

Isolated optical isomers may be purified from racemic mixtures bywell-known chiral separation techniques. According to one such method, aracemic mixture of a compound of the invention, or a chiral intermediatethereof, is separated into 99% wt. % pure optical isomers by HPLC usinga suitable chiral column, such as a member of the series of DAICEL®CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo,Japan). The column is operated according to the manufacturer'sinstructions.

Another well-known method of obtaining separate and substantially pureoptical isomers is classic resolution, whereby a chiral racemic compoundcontaining an ionized functional group, such as a protonated amine orcarboxylate group, forms diastereomeric salts with an oppositely ionizedchiral nonracemic additive. The resultant diastereomeric salt forms canthen be separated by standard physical means, such as differentialsolubility, and then the chiral nonracemic additive may be eitherremoved or exchanged with an alternate counter ion by standard chemicalmeans, or alternatively the diastereomeric salt form may retained as asalt to be used as a therapeutic agent or as a precursor to atherapeutic agent.

As used herein, the terms “stable compound” and “stable structure” aremeant to indicate a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into an efficacious therapeutic agent. Only stable compoundsare contemplated herein.

When a group is recited, wherein the group can be present in more than asingle orientation within a structure resulting in more than singlemolecular structure, e.g., a carboxamide group C(═O)NR, it is understoodthat the group can be present in any possible orientation, e.g.,X—C(═O)N(R)—Y or X—N(R)C(═O)—Y, unless the context clearly limits theorientation of the group within the molecular structure.

When a number of carbon atoms in a group, e.g., an alkyl, alkenyl,alkynyl, cycloalkyl, aryl, etc., is specified as a range, eachindividual integral number representing the number of carbon atoms isintended. For example, recitation of a (C₁-C₄)alkyl group indicates thatthe alkyl group can be any of methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, or tert-butyl. It is understood that aspecification of a number of carbon atoms must be an integer.

When a number of atoms in a ring is specified, e.g., a 3- to 9-memberedcycloalkyl or heterocyclyl ring, the cycloalkyl or heterocyclyl ring caninclude any of 3, 4, 5, 6, 7, 8, or 9 atoms. A cycloalkyl ring iscarbocyclic; a heterocyclyl ring can include atoms of any element inaddition to carbon capable of forming two or more bonds, e.g., nitrogen,oxygen, sulfur, and the like. The number of atoms in a ring isunderstood to necessarily be an integer.

Alkyl groups include straight chain and branched carbon-based groupshaving from 1 to about 20 carbon atoms, and typically from 1 to 12carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples ofstraight chain alkyl groups include those with from 1 to 8 carbon atomssuch as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl,and n-octyl groups. Examples of branched alkyl groups include, but arenot limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl,isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term“alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as wellas other branched chain forms of alkyl. Representative substituted alkylgroups can be substituted one or more times with any of the substituentgroups listed above, for example, amino, hydroxy, cyano, carboxy, nitro,thio, alkoxy, and halogen groups. Exemplary alkyl groups include, butare not limited to, straight or branched hydrocarbons of 1-6, 1-4, or1-3 carbon atoms, referred to herein as C₁₋₆alkyl, C₁₋₄alkyl, andC₁₋₃alkyl, respectively. Exemplary alkyl groups include, but are notlimited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl,3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, etc.

Cycloalkyl groups are groups containing one or more carbocyclic ringincluding, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, thecycloalkyl group can have 3 to about 8-12 ring members, whereas in otherembodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or7. Cycloalkyl groups further include polycyclic cycloalkyl groups suchas, but not limited to, norbornyl, adamantyl, bornyl, camphenyl,isocamphenyl, and carenyl groups, and fused rings such as, but notlimited to, decalinyl, and the like. Cycloalkyl groups also includerings that are substituted with straight or branched chain alkyl groupsas defined above. Cycloalkyl groups, unless otherwise specified, areunsubstituted.

Representative substituted cycloalkyl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2,2-, 2,3-,2,4-2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- ortri-substituted norbornyl or cycloheptyl groups, which can, if specifiedas such, be substituted with, for example, amino, hydroxy, cyano,carboxy, nitro, thio, alkoxy, and halogen groups. The term“cycloalkenyl” alone or in combination denotes a cyclic alkenyl group,i.e., a cycloalkyl including one or more carbon-carbon double bond.

The terms “carbocyclic,” “carbocyclyl,” and “carbocycle” denote a ringstructure wherein the atoms of the ring are carbon, such as a cycloalkylgroup or an aryl group. In some embodiments, the carbocycle has 3 to 8ring members, whereas in other embodiments the number of ring carbonatoms is 4, 5, 6, or 7. If specified as substituted, a carbocyclic ringcan be substituted with as many as N−1 substituents wherein N is thesize of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl,amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro,thio, alkoxy, and halogen groups, or other groups as are listed above. Acarbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or anaryl ring. A carbocyclyl can be monocyclic or polycyclic, and ifpolycyclic each ring can be independently be a cycloalkyl ring, acycloalkenyl ring, or an aryl ring.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groupsas defined above in which a hydrogen or carbon bond of the alkyl groupis replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkylgroups as defined above, except that at least one double bond existsbetween two carbon atoms. Thus, alkenyl groups have from 2 to about 20carbon atoms, and typically from 2 to 12 carbons or, in someembodiments, from 2 to 8 carbon atoms. Examples include, but are notlimited to vinyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.Exemplary alkenyl groups include, but are not limited to, a straight orbranched group of 2-6 or 3-4 carbon atoms, referred to herein asC₂₋₆alkenyl, and C₃₋₄alkenyl, respectively. Exemplary alkenyl groupsinclude, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

Alkynyl groups include straight and branched chain alkyl groups, exceptthat at least one triple bond exists between two carbon atoms. Thus,alkynyl groups have from 2 to about 20 carbon atoms, and typically from2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.Examples include, but are not limited to —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃),—CH₂C≡CH, —CH₂C≡C(CH₃), and —CH₂C≡C(CH₂CH₃) among others.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms in the ring. An aromatic compound, as is well-known in theart, is a multiply-unsaturated cyclic system that contains 4n+2 πelectrons where n is an integer. Thus aryl groups include, but are notlimited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl,fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl,chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In someembodiments, aryl groups contain about 6 to about 14 carbons in the ringportions of the groups. Aryl groups unless otherwise specified, areunsubstituted, as defined above. Representative substituted aryl groupscan be mono-substituted or substituted more than once, such as, but notlimited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substitutednaphthyl groups, which can be substituted with carbon or non-carbongroups such as those listed above.

Heterocyclyl groups or the term “heterocyclyl” includes aromatic andnon-aromatic ring compounds containing 3 or more ring members, of whichone or more ring atom is a heteroatom such as, but not limited to, N, O,and S. Thus a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl,or if polycyclic, any combination thereof. In some embodiments,heterocyclyl groups include 3 to about 20 ring members, whereas othersuch groups have 3 to about 15 ring members. A heterocyclyl groupdesignated as a C₂-heterocyclyl can be a 5-ring with two carbon atomsand three heteroatoms, a 6-ring with two carbon atoms and fourheteroatoms and so forth. Likewise a C₄-heterocyclyl can be a 5-ringwith one heteroatom, a 6-ring with two heteroatoms, and so forth. Thenumber of carbon atoms plus the number of heteroatoms sums up to equalthe total number of ring atoms. Ring sizes can also be expressed by thetotal number of atoms in the ring, e.g., a 3- to 10-memberedheterocyclyl group, counting both carbon and non-carbon ring atoms. Aheterocyclyl ring can also include one or more double bonds.Heterocyclyl groups, unless otherwise specified, are unsubstituted. Aheteroaryl ring is an embodiment of a heterocyclyl group. The term“heterocyclyl group” includes fused ring species including thosecomprising fused aromatic and non-aromatic groups. For example, adioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenylring system) are both heterocyclyl groups within the meaning herein. Theterm also includes polycyclic, e.g., bicyclo- and tricyclo-ring systemscontaining one or more heteroatom such as, but not limited to,quinuclidyl.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12ring members. A heteroaryl group is a variety of a heterocyclyl groupthat possesses an aromatic electronic structure, which is amultiply-unsaturated cyclic system that contains 4n+2 π electrons,wherein n is an integer. A heteroaryl group designated as aC₂-heteroaryl can be a 5-ring (i.e., a 5-membered ring) with two carbonatoms and three heteroatoms, a 6-ring (i.e., a 6-membered ring) with twocarbon atoms and four heteroatoms and so forth. Likewise a C₄-heteroarylcan be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, andso forth. The number of carbon atoms plus the number of heteroatoms sumsup to equal the total number of ring atoms. Heteroaryl groups include,but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl,azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinylgroups. Heteroaryl groups, unless otherwise specified, areunsubstituted. Representative substituted heteroaryl groups can besubstituted one or more times with independently selected groups such asthose listed above.

The terms “halo” or “halogen” or “halide” by themselves or as part ofanother substituent mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.

A “haloalkyl” group includes mono-halo alkyl groups, poly-halo alkylgroups wherein all halo atoms can be the same or different, and per-haloalkyl groups, wherein all hydrogen atoms are replaced by the same ordiffering halogen atoms, such as fluorine and/or chlorine atoms.Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl,1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, andthe like.

A “haloalkoxy” group includes mono-halo alkoxy groups, poly-halo alkoxygroups wherein all halo atoms can be the same or different, and per-haloalkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms,such as fluoro. Examples of haloalkoxy include trifluoromethoxy,1,1-dichloroethoxy, 1,2-di chloroethoxy,1,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.

Standard abbreviations for chemical groups such as are well known in theart are used; e.g., Me=methyl, Et=ethyl, i-Pr=isopropyl, Bu=butyl,t-Bu=tert-butyl, Ph=phenyl, Bn=benzyl, Ac=acetyl, Bz=benzoyl, and thelike.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compounds of thepresent invention may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds of theinvention. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility inprocess of synthesis, purification or formulation of compounds of theinvention. “Pharmaceutically or pharmacologically acceptable” includemolecular entities and compositions that do not produce an adverse,allergic or other untoward reaction when administered to an animal, or ahuman, as appropriate. For human administration, preparations shouldmeet sterility, pyrogenicity, and general safety and purity standards asrequired by FDA Office of Biologics standards.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described. Moreover, where features or aspects ofthe invention are described in terms of Markush groups, those skilled inthe art will recognize that the invention is also thereby described interms of any combination of individual members or subgroups of membersof Markush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

If a value of a variable that is necessarily an integer, e.g., thenumber of carbon atoms in an alkyl group or the number of substituentson a ring, is described as a range, e.g., 0-4, what is meant is that thevalue can be any integer between 0 and 4 inclusive, i.e., 0, 1, 2, 3, or4.

In various embodiments, the compound or set of compounds, such as areused in the inventive methods, can be any one of any of the combinationsand/or sub-combinations of the above-listed embodiments.

In various embodiments, a compound as shown in any of the Examples, oramong the exemplary compounds, is provided. Provisos may apply to any ofthe disclosed categories or embodiments wherein any one or more of theother above disclosed embodiments or species may be excluded from suchcategories or embodiments.

The compounds described herein can be prepared in a number of ways basedon the teachings contained herein and synthetic procedures known in theart. In the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be chosen to be the conditionsstandard for that reaction, unless otherwise indicated. It is understoodby one skilled in the art of organic synthesis that the functionalitypresent on various portions of the molecule should be compatible withthe reagents and reactions proposed. Substituents not compatible withthe reaction conditions will be apparent to one skilled in the art, andalternate methods are therefore indicated. The starting materials forthe examples are either commercially available or are readily preparedby standard methods from known materials. All commercially availablechemicals were obtained from Aldrich, Alfa Aesare, Wako, Acros, Fisher,Fluka, Maybridge or the like and were used without further purification,except where noted. Dry solvents are obtained, for example, by passingthese through activated alumina columns.

The present invention further embraces isolated compounds of theinvention. The expression “isolated compound” refers to a preparation ofa compound of the invention, or a mixture of compounds the invention,wherein the isolated compound has been separated from the reagents used,and/or byproducts formed, in the synthesis of the compound or compounds.“Isolated” does not mean that the preparation is technically pure(homogeneous), but it is sufficiently pure to compound in a form inwhich it can be used therapeutically. Preferably an “isolated compound”refers to a preparation of a compound of the invention or a mixture ofcompounds of the invention, which contains the named compound or mixtureof compounds of the invention in an amount of at least 10 percent byweight of the total weight. Preferably the preparation contains thenamed compound or mixture of compounds in an amount of at least 50percent by weight of the total weight; more preferably at least 80percent by weight of the total weight; and most preferably at least 90percent, at least 95 percent or at least 98 percent by weight of thetotal weight of the preparation.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures and purified by standard techniques such asfiltration, liquid-liquid extraction, solid phase extraction,distillation, recrystallization, or chromatography, including flashcolumn chromatography, or HPLC.

Another aspect of an embodiment of the invention provides compositionsof the compounds of the invention, alone or in combination with anothermedicament. As set forth herein, compounds of the invention includestereoisomers, tautomers, solvates, prodrugs, pharmaceuticallyacceptable salts and mixtures thereof. Compositions containing acompound of the invention can be prepared by conventional techniques,e.g. as described in Remington: The Science and Practice of Pharmacy,19th Ed., 1995, or later versions thereof, incorporated by referenceherein. The compositions can appear in conventional forms, for examplecapsules, tablets, aerosols, solutions, suspensions or topicalapplications.

It is within ordinary skill to evaluate any compound disclosed andclaimed herein for effectiveness in inhibition of a sphingosine kinase,such as sphingosine kinase type 1 or sphingosine kinase type 2, and inthe various cellular assays using the procedures described above orfound in the scientific literature. Accordingly, the person of ordinaryskill can prepare and evaluate any of the claimed compounds withoutundue experimentation.

Any compound found to be an effective inhibitor of sphingosine kinasecan likewise be tested in animal models and in human clinical studiesusing the skill and experience of the investigator to guide theselection of dosages and treatment regimens.

In some embodiments, the invention provides a compound according toformula (I)

wherein

-   -   X is phenyl, indolyl, or naphthyl;    -   R¹ and R² are independently selected from the group consisting        of H, OH, —(C₁-C₆)alkyl-OH, halo, NH₂, NOH, NHOH, and CN;    -   or R¹ and R², if bound to adjacent carbon atoms, in combination        with the existing carbon-carbon bond represent a double bond        between the adjacent carbon atoms;    -   R³ and R⁴ are independently selected from the group consisting        of H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₆)haloalkyl, CN, and        halo;    -   m=0 or 1;    -   W is CH₂, O or, NH,    -   V is selected from the group consisting of H, (C₁-C₁₀)alkyl,        (C₂-C₁₂)alkenyl, —(C₁-C₁₀)alkyl-(C₆-C₁₀)aryl,        —(C₂-C₁₂)alkenyl-(C₆-C₁₀)aryl,        —(C₁-C₁₀)alkyl-(C₆-C₁₀)aryl-(C₁-C₁₀)alkyl,        —(C₁-C₁₀)alkyl-(C₃-C₈)cycloalkyl, —(C₁-C₁₀)alkyl-heterocyclyl        containing from 1 to 3 ring heteroatoms selected from N, O, and        S;    -   wherein any aryl is optionally fused to (C₆-C₁₀)aryl,        (C₃-C₈)cycloalkyl, or heterocyclyl containing from 1 to 3 ring        heteroatoms selected from N, O, and S    -   wherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, or aryl is        optionally substituted by 1-4 substituents independently        selected from the group consisting of F, Cl, Br, (C₁-C₆)alkyl,        —O—(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl,        and CN;    -   Y¹, Y², and Y³ are independently selected from the group        consisting of C, N, NH, O, and S;        or a pharmaceutically acceptable salt thereof.

The invention also provides, in various embodiments, some formula (I)compounds that conform to formula (II):

wherein:

R¹ and R² are H, or when m=1, one of R¹ and R² can be OH;

R³ and R⁴ are each independently H, (C₁-C₄)alkyl, cyclopropyl,(C₁-C₂)fluoroalkyl, cyano, or halo;

m=0 or 1;

each of Y¹, Y², and Y³ is independently selected from the groupconsisting of C, N, NH, O, and S;

-   -   X is a phenyl, naphthyl, or indolyl;    -   W is O or CH₂;    -   V is (C₅-C₁₀)alkyl;        or a pharmaceutically acceptable salt thereof.

The invention provides in some formula I compounds wherein m is 1; andY¹ is N; Y² is N and Y³ is O; or Y² is O and Y³ is N. Thus, the centralring in these embodiments is an oxadiazole.

In some embodiments, optionally in combination with any otherembodiment, R¹ and R² are independently selected from the groupconsisting of H, OH, CH₂OH, F, and Cl. For instance, some formula (I)compounds provide for R¹ and R² as both hydrogen.

Optionally in combination with any other embodiment, some formula (I)compounds have X as phenyl and one of R³ and R⁴ as —CF₃. For example, insome formula (I) compounds R³ is trifluoromethyl and R⁴ is hydrogen.

Formula (II) compounds, a selection of Formula (I), also constitutevarious embodiments of the invention. In some Formula (II) compounds,according to some embodiments, the ring comprising Y¹, Y², and Y³ is anoxadiazole ring. In other embodiments, the ring comprising Y¹, Y², andY³ is a thiadiazole ring.

In accordance with another embodiment, the invention provides Formula(II) compounds in which R¹ and R² are both hydrogen. In others, X isphenyl. Exemplary compounds satisfying these structural requirements arethose in which m is 1 and R² is OH. In other embodiments, X is naphthylor indolyl.

Formula I compounds are N-hydroxylated derivatives of, and in someembodiments they also are prodrugs of, SPHK1 and SPHK2 inhibitors listedbelow in Table 1. The compounds as shown in Table 1 are shown in theform of the salt as which they were isolated, but a compound can also bethe free base form of the structure shown in Table 1, or can be a saltof that free base form other than the specific salt shown.

Table 1 below provides data with respect to the inhibitory bioactivityof the indicated exemplary compound versus human sphingosine kinase type1 (hSPHK1) and human sphingosine kinase type 2 (hSPHK2), wherein A, Band C indicate range estimates of K_(I) values at recombinant humanSPHK1 and SPHK2; A<1 micromolar, B 1-10 micromolar, and C>10 micromolar.

TABLE 1 Exemplary Compounds and Bioactivity Cpd activity activity #Structure hSPHK1 hSPHK2 1B

C A 2B

C A 3B

C A 4B

C A 5B

C A 6B

C A 7B

C A 8B

C A 9B

C A 10B

C A 11B

C A 12B

B A 13B

B A 14B

A A 1A

C C 2A

C C 3A

B A 4A

C B 5A

C A 6A

A A 7A

B A 8A

C A 9A

C C 10A

C C 11A

C C 12A

C C 13A

C B 14A

C C 15A

B C 16A

C C 17A

C A 18A

C B 19A

C C 20A

A A 21A

C A 22A

B A 23A

B A 24A

B A 25A

A A 26A

C A 27A

C B 28A

B A 29A

C C 30A

C A 31A

C A 32A

C A 33A

C A 34A

B A 35A

C A 36A

C A 37A

B A 38A

C B 39A

C A 40A

B A 41A

B A 42A

C A 43A

B A 44A

C B 45A

C B 46A

C C 47A

C B 48A

C B 49A

C A 50A

C A 51A

C C 52A

C B 53A

C B 54A

C C 55A

C C 56A

C B 57A

C C 58A

C C 59A

C C 60A

C C 61A

C A 62A

C C 63A

A A 64A

C C 65A

C C 66A

C C 67A

C B 68A

C C 69A

C C 70A

C B 71A

C C 72A

C B 73A

C C 74A

C B 75A

C C 76A

C A 77A

C C 78A

C A 79A

C C 80A

C B 81A

C A 82A

C A 83A

C A 84A

C A 85A

C A 86A

C A 87A

C A 88A

C A 89A

C C 90A

C A 91A

C A 92A

C A 93A

C C 94A

C A 95A

B A 96A

A A

Specific embodiments of the invention are Formula I compounds as shownbelow in Table 2.

TABLE 2 Exemplary Formula I Compounds Cpd. # Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

In various embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention and apharmaceutically acceptable excipient. Suitable excipients and dosageforms are discussed above.

The amidoxime compounds of the invention exhibit far greater oralavailability than their counterparts without N-hydroxylation on theguanadino moiety. When the inventive compounds are reduced, they revealthe active drugs that are highly potent and selective inhibitors ofhSPHK2, having sub-micromolar K_(I) values. For instance, activecompounds can have a K_(I) for hSPHK2 in the sub-micromolar range, whilethe K_(I) for hSPHK1 can be greater than 1 micromolar, or can be greaterthan 10 micromolar.

Potential uses of Formula I compounds include, but are not limited to,anti-angiogenesis, treating neoplastic disease, treating autoimmunedisorders, treating disease characterized by inflammation, treatingdiseases characterized by fibrosis, and treating vascular injury, suchas acute lung injury, sepsis, capillary and vascular leak syndromes,pneumonia, ischemia reperfusion injury, acute kidney injury, as well asenhancing the delivery of therapeutics by improving the integrity ofvascular barriers (e.g., Blood Brain Barrier) in diseases where they aredisrupted such as, but not limited to cancer and Alzheimer's disease. Invarious embodiments of the invention, the method of treating any of theforegoing conditions may include administration of an antagonist of anyone, or combination thereof, of S1P1, S1P2, S1P3, S1P4, and S1P5.

Formula I compounds also are used to treat autoimmune and inflammatoryconditions, i.e., immunomodulate components of the immune system. Hence,in various embodiments of the invention, the SphK inhibitors, onceliberated, may affect the cell signaling events associated with, but notlimited to, the following interleukins, cytokines, and immunomodulators:a) members of the interleukin-1 (IL-1) family; b) interleukin 2 (IL-2);c) interleukin 4 (IL-4); d) interleukin 5 (IL-5); e) interleukin-6(IL-6); f) interleukin-12 (IL-12); g) interleukin 13 (IL-13); h)interleukin-23 (IL-23); i) tumor necrosis factor (TNF) alpha; and j)interferon gamma. For example, an inventive compound can be used totreat a disease that is at least in part characterized by theover-expression or undesirable cell-signaling activities mediated by anyof the above factors. Thus, in various embodiments, the presentlydisclosed subject matter provides a method for preventing, treating,managing, and/or ameliorating an autoimmune or inflammatory disorder orone or more symptoms thereof, said method comprising administering to asubject in need thereof a prophylactically and/or therapeuticallyeffective amount of a compound of the presently disclosed subject matterand a prophylactically or therapeutically effective amount of one ormore immunomodulatory agents.

Formula I compounds are also useful for the treatment of diseases ordisorders that are associated with excessive vascular permeability.Thus, provided herein is a method of treating or preventing these or anyother disease associated with an increase in vascular permeability oredema. For example, inhibiting edema formation should be beneficial tooverall patient outcome in situations such as inflammation, allergicdiseases, cancer, cerebral stroke, myocardial infarction, pulmonary andcardiac insufficiency, renal failure, and retinopathies, to name a few.Furthermore, as edema is a general consequence of tissue hypoxia, it canalso be concluded that inhibition of vascular leakage represents apotential approach to the treatment of tissue hypoxia. For example,interruption of blood flow by pathologic conditions (such as thrombusformation) or medical intervention (such as cardioplegia, organtransplantation, and angioplasty) could be treated both acutely andprophylactically using inhibitors of vascular leakage.

Ischemia/reperfusion injury following stroke and myocardial infarctionis also characterized by vascular permeability and edema. A deficit intissue perfusion leads to persistent post-ischemic vasogenic edema,which develops as a result of increased vascular permeability. Tissueperfusion is a measure of oxygenated blood reaching the given tissue dueto the patency of an artery and the flow of blood in an artery. Tissuevascularization may be disrupted due to blockage, or alternatively, itmay result from the loss of blood flow resulting from blood vesselleakage or hemorrhage upstream of the affected site. The deficit intissue perfusion during acute myocardial infarction, cerebral stroke,surgical revascularization procedures, and other conditions in whichtissue vascularization has been disrupted, is a crucial factor inoutcome of the patient's condition. Edema can cause various types ofdamage including vessel collapse and impaired electrical function,particularly in the heart. Subsequent reperfusion, however, can alsocause similar damage in some patients, leading to a treatment paradox.While it is necessary, to unblock an occluded blood vessel or to repairor replace a damaged blood vessel, the ensuing reperfusion can, in somecases, lead to further damage. Likewise, during bypass surgery, it isnecessary to stop the heart from beating and to have the patient hookedto a heart pump. Some patients who undergo bypass surgery, for example,may actually experience a worsening of condition (“post-pump syndrome”),which may be the result of ischemia during cessation of cardiac functionduring surgery. An arterial blockage may cause a reduction in the flowof blood, but even after the blockage is removed and the artery isopened, if tissue reperfusion fails to occur, further tissue damage mayresult. For example, disruption of a clot may trigger a chain of eventsleading to loss of tissue perfusion, rather than a gain of perfusion.

Additional diseases and disorders characterized by undesirable vascularpermeability include, for example, infectious and non-infectiousdiseases that may result in a cytokine storm. A cytokine storm can beprecipitated by a number of infectious and non-infectious diseasesincluding, for example, graft versus host disease (GVHD), adultrespiratory distress syndrome (ARDS), sepsis, avian influenza, smallpox,and systemic inflammatory response syndrome (SIRS).

Accordingly, in various embodiments, the invention can provide a methodof inhibiting a sphingosine kinase, comprising contacting thesphingosine kinase with an effective amount or concentration of acompound of formula (I) of the invention, or an effective amount of apharmaceutical composition of the invention. For example, thesphingosine kinase can be sphingosine kinase type 1 or sphingosinekinase type 2, or both.

In various embodiments the compound of formula (I) liberates a selectiveinhibitor of one of sphingosine kinases type 1 or type 2 relative to theother of sphingosine kinases type 1 or type 2.

The invention provides, in various embodiments, a method of inhibitingangiogenesis in a tumor, comprising contacting the tumor with aneffective amount or concentration of a compound of formula (I).

The invention provides, in various embodiments, a method of treatment ofa patient afflicted by a neoplastic disease, comprising administering tothe patient an effective dose of a compound of formula (I). For example,the effective dose of the compound of formula (I) can inhibit tumorgrowth, metastasis, or angiogenesis. More specifically, the compound offormula (I) can inhibit angiogenesis associated with the neoplasticdisease, such as by regulation of S1P levels in tissue or serum.

The invention provides, in various embodiments, a method of treatment ofa disease in a patient afflicted therewith, wherein the disease involvesexcess vascular growth, comprising administering to the patient aneffective dose of a compound of formula (I). For example, the diseasecan be macular degeneration or diabetic retinopathy. More specifically,administering to the patient can comprise injecting a pharmaceuticalcomposition comprising an effective dose of a compound of formula (I)into the posterior eye in depot form.

The invention provides, in various embodiments, a method of treatment ofan allergic disease in a patient afflicted therewith, comprisingadministering to the patient an effective dose of a compound of formula(I). For example, the allergic disease can be asthma. The asthma can bedue to overproduction of Th2 cytokines.

The invention provides, in various embodiments, a method of treatment ofan inflammatory disease of the eye in a patient afflicted therewith,comprising administering to the patient an effective dose of a compoundof formula (I). For example, the disease of the eye can be uveitis,scleritis, or vitritis.

The invention provides, in various embodiments, a method of treatment ofan inflammatory disease of the kidney in a patient afflicted therewith,comprising administering to the patient an effective dose of a compoundof formula (I). More specifically, the inflammatory disease of thekidney can be glomerulonephritis, glomerular injury, nephrotic syndrome,interstitial nephritis, lupus nephritis, Goodpasture's disease,Wegener's granulomatosis, renal vasculitis, IgA nephropathy, diabeticnephropathy, chronic allograft nephropathy, or idiopathic glomerulardisease.

The invention provides, in various embodiments, a method of treatment ofa fibrotic disease in a patient afflicted therewith, comprisingadministering to the patient an effective dose of a compound of formula(I). For example, the fibrotic disease can be pulmonary fibrosis, renalfibrosis, cardiac fibrosis, or hepatic fibrosis.

The invention provides, in various embodiments, a method of treatment ofa patient afflicted with any of acute lung injury, sepsis, capillaryleak syndrome, pneumonia, ischemia reperfusion injury, acute kidneyinjury, diabetic nephropathy, age-related macular degeneration, diabeticretinopathy, pulmonary fibrosis, or renal fibrosis, comprisingadministering to the patient an effective dose of a compound of formula(I).

The invention provides, in various embodiments, a method of enhancingdelivery of a therapeutic agent to a patient by improving the integrityof a vascular barrier in a disease where the vascular barrier isdisrupted, comprising administering to the patient an effective dose ofa compound of formula (I). More specifically, the disease can be canceror Alzheimer's disease. The vascular barrier can be the blood-brainbarrier.

The invention provides, in various embodiments, a method of medicaltreatment of disease in a patient afflicted therewith, wherein thetreatment involves the regulation of endothelial cell barrier functionas a result of the inhibition of sphingosine kinase enzymatic activity,comprising administering to the patient an effective dose of a compoundof Formula (I). For example, the disease can be acute lung injury,sepsis, capillary leak syndrome, pneumonia, ischemia reperfusion injury,acute kidney injury, diabetic nephropathy, age-related maculardegeneration, diabetic retinopathy, pulmonary fibrosis, or renalfibrosis. For example, the compound of formula (I) can be a selectiveinhibitor of sphingosine kinase type 2. The administration of theeffective dose of the compound of formula (I) can increase blood levelsof sphingosine-1-phosphate.

The invention provides, in various embodiments, a method of treatment ofan autoimmune disease in a patient afflicted therewith, comprisingadministering to the patient an effective dose of a compound of formula(I). For example, the autoimmune disease can be multiple sclerosis, typeI diabetes, inflammatory bowel diseases, Crohn's disease, ulcerativecolitis, Grave's disease, Addison's disease, dermatomyositis, myastheniagravis, systemic lupus erythematosus, scleroderma, or psoriasis.

The invention provides, in various embodiments, a method of treatment ofatherosclerosis in a patient afflicted therewith, comprisingadministering to the patient an effective dose of a compound of formula(I).

The invention provides, in various embodiments, a method of treatment ofpulmonary arterial hypertension in a patient afflicted therewith,comprising administering to the patient an effective dose of a compoundof formula (I).

In any of the methods of treatment and medical uses disclosed andclaimed herein, the compound of formula (I) can be any of theembodiments of the compound as disclosed in Table 1, or as covered byany of the generic and subgeneric descriptions of the bioactiveinhibitor of a sphingosine kinase.

Materials and Methods

Recombinant baculovirus encoding human sphingosine kinase type 1 (SPHK1)was used to infect Sf9 insect cells and after 2-5 days, cleared lysateswere prepared and used without further purification. Human SPHK2, whichwas partially purified from baculovirus-infected Sf9 cell lysates, waspurchased from a commercial source. Sphingosine kinase assays wereperformed using standard protocols. Product [³²P]S1P was recovered bybinding to cation exchange paper and quantified by scintillationcounting. In some cases, [³²P]S1P was recovered by organic extraction,displayed by thin layer chromatography, recovered and quantified byscintillation counting.

EXAMPLES Example 1: Synthesis and Characterization of(S)-amino(2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (2A)

Scheme 1 below exemplifies synthetic methodology for making compounds ofFormulae IA and IB. With the exception of final compound 2A, compoundnumbering in Scheme 1 pertains only to the depicted compounds.

4-(octyloxy)-3-(trifluoromethyl)benzonitrile 15

(4-(Trifluoromethyl)phenyl)methanol (500 mg, 2.67 mmol), 1-bromooctane(0.55 mL, 3.21 mmol), and potassium carbonate (1.5 g, 10.69 mmol) wereadded to ACN (21 mL) and refluxed overnight. Reaction was checked forcompletion. After completed, the mixture was cooled to room temperatureand partitioned between ethyl acetate and water. Organic layers werethen washed with brine and dried with sodium sulfate. The resultingmixture was filtered and concentrated in vacuo. The residue was purifiedby silica gel column chromatography (10% ethyl acetate/hexanes) to yield15 (750 mg, 94%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d,J=2.0 Hz, 1H), 7.75 (dd, J=8.7, 2.1 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H),4.10 (t, J=6.4 Hz, 2H), 1.87-1.77 (m, 2H), 1.46 (p, J=7.1 Hz, 2H),1.38-1.14 (m, 8H), 0.85 (t, J=6.1 Hz, 3H); ¹¹C NMR (101 MHz, CDCl₃) δ160.3, 137.5, 131.3 (³J_(CF)=4.7 Hz), 122.4 (¹J_(CF)=273.4 Hz), 120.0(q, ²J_(CF)=31.3 Hz), 117.9, 113.5, 103.4, 69.5, 31.7, 29.1, 29.1, 28.7,25.7, 22.6, 14.0; ¹⁹F NMR (376 MHz, CDCl₃) δ −63.4 (s, 3F).

(Z)—N′-hydroxy-4-(octyloxy)-3-(trifluoromethyl)benzimidamide 16

15 (750 mg, 2.5 mmol) was dissolved in ethanol (13 mL). Triethylamine(1.15 mL, 8.27 mmol) and hydroxylamine hydrochloride (348 mg, 5.01 mmol)was added and the reaction mixture was refluxed overnight. The organicsolvent was removed under reduced pressure and the residue was purifiedby silica gel column chromatography (50% ethyl acetate/hexanes) to yield16 (700 mg, 84%) as white solid. ¹H NMR (400 MHz, Methanol-d₄) δ 7.89(d, J=2.1 Hz, 1H), 7.82 (dd, J=8.7, 2.2 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H),4.17 (t, J=6.2 Hz, 2H), 1.86-1.75 (m, 2H), 1.51 (p, J=7.1 Hz, 2H),1.41-1.23 (m, 8H), 0.91 (t, J=6.6 Hz, 3H); ¹³C NMR (101 MHz,Methanol-d₄) δ 159.3, 154.1, 132.4, 125.9 (q, ³J_(CF)=5.3 Hz), 125.0 (q,¹J_(CF)=273.1 Hz), 119.6 (q, ²J_(CF)=30.9 Hz), 113.9, 69.9, 32.9, 30.3,30.3, 30.1, 26.9, 23.7, 14.4; ¹⁹F NMR (376 MHz, Methanol-d₄) δ −63.7 (s,3F); HRMS (ESI+): Calcd for C₁₆H₂₄F₃N₂O₂ [M+H]: 333.1789, Found:333.1778.

(S)-tert-butyl2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate17

DIEA (0.66 mL, 3.79 mmol) was added to a solution of(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (554 mg, 2.53mmol) and 16 (700 mg, 2.11 mmol) in DMF (11 mL). HCTU (1.3 g, 3.16 mmol)was then added to the resulting mixture at room temperature and stirredat 100° C. overnight. At this time, TLC showed complete conversion ofstarting material. The solution was partitioned between ethyl acetateand LiBr aqueous solution. The aqueous solution was extracted with ethylacetate and the combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated via vacuum. The residue was purified bysilica gel column chromatography (100% CH₂Cl₂ then switched to 15% ethylacetate/hexanes) to yield 17 (690 mg, 64%) as an oil. ¹H NMR (400 MHz,CDCl₃) δ 8.28 (s, 1H), 8.18 (d, J=8.7 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H),5.26-4.85 (m, 1H), 4.11 (t, J=6.2 Hz, 2H), 3.76-3.64 (m, 1H), 3.62-3.44(m, 1H), 2.48-2.31 (m, 1H), 2.21-2.10 (m, 2H), 2.07-1.96 (m, 1H), 1.84(p, J=6.7 Hz, 2H), 1.53-1.43 (m, 5H), 1.39-1.22 (m, 14H), 0.88 (t, J=6.5Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 180.9, 167.4, 159.4, 153.6, 132.5,126.5, 123.6 (q, ¹J_(CF)=275.9 Hz), 119.8, 118.6, 113.0, 80.6, 69.2,53.9, 46.5, 32.5, 31.9, 31.6, 29.3, 29.0, 28.3, 25.9, 24.5, 23.8, 22.8,14.2; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.8 (d, J=15.1 Hz, 3F); HRMS (ESI+):Calcd for C₂₆H₃₆F₃N₃O₄Na [M+Na]: 534.2555, Found: 534.2506.

(S)-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-ium2,2,2-trifluoroacetate 18

17 (690 mg 1.35 mmol) was dissolved in dichloromethane (3.4 mL).Trifluoroacetic acid (3.4 mL) was added to the reaction mixture and themixture was stirred 1-2 hours open to air at room temperature. Theorganic solvent was then removed under reduced pressure. The residue wasconcentrated via vacuum to yield 18 as a yellow oil. ¹H NMR (400 MHz,Methanol-d₄) δ 8.26 (d, J=7.4 Hz, 2H), 7.32 (d, J=9.4 Hz, 1H), 5.18 (t,J=7.8 Hz, 1H), 4.17 (t, J=6.2 Hz, 2H), 3.67-3.45 (m, 2H), 2.70-2.60 (m,1H), 2.48-2.34 (m, 1H), 2.33-2.16 (m, 2H), 1.88-1.76 (m, 2H), 1.50 (p,J=7.1 Hz, 2H), 1.41-1.22 (m, 8H), 0.88 (t, J=6.7 Hz, 3H); ¹³C NMR (101MHz, Methanol-d₄) δ 176.3, 168.7, 161.0, 134.0, 127.3 (q, ³J_(CF)=5.5Hz), 124.6 (q, ¹J_(CF)=274.9 Hz), 120.3 (q, ²J_(CF)=39.0 Hz), 119.0,114.9, 70.3, 55.5, 47.3, 32.9, 30.3, 30.2, 30.0, 26.9, 24.5, 23.7, 14.4;¹⁹F NMR (376 MHz, CDCl₃) δ −64.2 (s, 3F); HRMS (ESI+): Calcd forC₂₁H₂₉F₃N₃O₂+[M+]: 412.2211, Found: 412.2215.

(S,Z)-tert-butyl(((tert-butoxycarbonyl)amino)(2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate20

DIEA (0.1 mL, 0.50 mmol) was added to a solution of 19 (34 mg, 0.08mmol) and (Z)-tert-butyl(((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (20 mg,0.07 mmol) in acetonitrile (0.4 mL). The resulting reaction mixture wasthen stirred at room temperature for 3 days. The organic solvent wasremoved under reduced pressure and the residue was purified by silicagel column chromatography (2:1 ethyl acetate:hexane) to yield 20 (24 mg,45%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=2.0 Hz, 1H),8.18 (dd, J=8.7, 2.1 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 5.60 (dd, J=7.8,4.5 Hz, 1H), 4.11 (t, J=6.4 Hz, 2H), 3.94-3.75 (m, 2H), 2.50-2.40 (m,1H), 2.30-2.12 (m, 2H), 2.08-1.99 (m, 1H), 1.89-1.77 (m, 2H), 1.56-1.22(m, 27H), 0.88 (t, J=6.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 179.3,167.4, 162.1, 159.4, 153.8, 150.5, 132.6, 126.9 (q, ³J_(CF)=5.0 Hz),123.4 (q, ¹J_(CF)=276.7 Hz), 119.5 (q, ²J_(CF)=33.3 Hz), 113.0, 110.2,82.4, 79.7, 69.2, 55.4, 49.6, 31.9, 29.8, 29.3, 29.0, 28.2, 28.1, 25.9,22.8, 14.2; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.8 (s, 3F); HRMS (ESI+): Calcdfor C₃₂H₄₇F₃N₅O₆ [M+H]: 654.3478, Found: 654.3506.

(S)-amino(2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (2A)

Hydrogen chloride gas is passed through a solution of 20 (9 mg, 0.01mmol) in methanol (1 mL) for 5 minutes. The organic solvent was thenremoved under reduced pressure to yield 2 (5 mg, 80%) as white solid. ¹HNMR (400 MHz, Methanol-d₄) δ 8.27 (dd, J=8.6, 2.1 Hz, 2H), 8.24 (d,J=2.0 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 5.46 (dd, J=7.9, 1.7 Hz, 1H),4.20 (t, J=6.2 Hz, 2H), 3.80 (td, J=9.5, 2.5 Hz, 1H), 3.64 (td, J=9.6,7.4 Hz, 1H), 2.65-2.47 (m, 2H), 2.30-2.21 (m, 1H), 2.19-2.04 (m, 1H),1.90-1.81 (m, 2H), 1.54 (p, J=6.7 Hz, 2H), 1.46-1.30 (m, 8H), 0.92 (t,J=6.7 Hz, 3H); ¹³C NMR (126 MHz, Methanol-d₄) δ 179.2, 168.6, 160.9,157.1, 133.9, 127.1 (q, ³J_(CF)=5.5 Hz), 124.8 (q, ¹J_(CF)=272.8 Hz),120.3 (q, ²J_(CF)=29.9 Hz), 119.3, 114.8, 70.3, 56.5, 32.9, 32.7, 30.3,30.2, 30.0, 26.9, 24.3, 23.7, 14.4; ¹⁹F NMR (376 MHz, Methanol-d₄) δ−64.2 (s, 3F); HRMS (ESI+): Calcd for C₂₂H₃₁F₃N₅O₂+[M+]: 454.2429,Found: 454.2435.

Examples 2-14: Synthesis and Characterization of Formula IA and IBCompounds Wherein X is Indolyl

Scheme 2 outlines general synthetic methodology for the preparation ofCompound Nos 1A-4A, 7A, 8B, 9B, 10B, 11B, 17A, 18A, 74A, 75A. Compoundnumbering in Scheme 2 is internal to the Scheme, while the subsequentprocedures refer where applicable to the final compounds.

General Procedures (Scheme 2) General Procedure 1: Amidoxime Formation

Cyanoindole 1a-d (1 equiv.) and hydroxylamine hydrochloride (3 equiv.),and TEA (3 equiv.) were added to a round bottom flask containingethanol. The reaction mixture was heated to 80° C. for 12 hours or untilthe reaction appeared to have gone to completion via monitoring by TLC.The solution was cooled to room temperature and the solvent was removedunder reduced pressure. The resulting solid was loaded onto celite andpurified on a silica gel column with 0-10% methanol in ethyl acetate.

General Procedure 2: 1,2,4-Oxadiazole Formation

Amidoxime 2a-d (1 equiv.), Boc-L-Proline (1.4 equiv.), and DIEA (1.4equiv.) were added to a round bottom flask containing DMF. After addingHCTU (1.8 equiv.) to the reaction, the solution was heated to 120° C.for 12-16 hours. Once the reaction cooled to room temperature, thesolution was extracted with ethyl acetate and saturated LiBr solution.The combined organic layers were washed with brine and dried over sodiumsulfate. After filtration to remove the sodium sulfate and concentrationvia reduced pressure, the resulting brown oil was purified on a silicacolumn with hexane and ethyl acetate.

General Procedure 3: N-alkylation of Indole

Indole 3a-d was added to a round bottom flask which was subsequentlypurged with nitrogen and sealed with a rubber septum. The flask wasplaced in an ice bath and DMF (1 mL) was added. Sodium hydride (1.5equiv.) was added to the flask in one addition and the septum wasreplaced on the vessel. The reaction mixture was stirred for 30 minutesat 0° C. and the ice bath was replenished. Alkyl halide (3 equiv.) wasadded to the cooled solution drop-wise. The reaction solution wasstirred for an additional 30 minutes while the solution warmed to roomtemperature. The reaction was quenched with the slow addition of D.I.water. The product was extracted with ethyl acetate and saturated LiBr.The combined organic layers were washed with brine and dried over sodiumsulfate. After filtration and concentration via reduced pressure, theresulting oil was purified on a silica column with hexane and ethylacetate.

General Procedure 4: Boc-deprotection

Boc-amine 4e-w or Di-Boc-guanidine 6e-w was dissolved in methanol. HClgas was bubbled into the solution for 1 minute. The solution was stirreduntil TLC indicated that all of the Boc-protected amine had beenconsumed. The solvent was removed under reduced pressure. The resultingwhite to light yellow solid was washed with diethyl ether to yield pureproduct.

General Procedure 5: Guanylation of Secondary Amines

Hydrogen chloride salt of 5e-w (1 equiv.) was added to a round bottomflask with acetonitrile and DIEA (3 equiv.). The solution was allowed tostir for 10 minutes before being transferred to a microwave vialcontaining (Z)-Tert-butyl(((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (1.05equiv). The vessel was capped and placed in the CEM microwave where itwas heated to 80° C. for 2 hours. The solvent was removed under reducedpressure and the resulting yellow oil was purified on silica gel withhexanes and ethyl acetate to yield pure product.

Characterization (Scheme 2) N′-hydroxy-1H-indole-3-carboximidamide (2a)

2a was prepared using general procedure 1. Purification on a silica gelcolumn with 70-100% ethyl acetate in hexanes produced 2a as a mixture ofenantiomers (0.61 g, 99%), a tan solid. ¹H NMR (400 MHz, CD₃OD) δ8.14-8.10 (m, 0.4H), 7.96 (ddd, J=7.9, 1.3, 0.8 Hz, 1H), 7.92 (s, 0.4H),7.61 (s, 1H), 7.43-7.40 (m, 0.4H), 7.40-7.36 (m, 1H), 7.19-7.06 (m, 3H).¹³C NMR (101 MHz, CD₃OD) δ 173.06, 170.88, 153.79, 138.03, 130.13,126.08, 123.42, 123.24, 122.06, 121.68, 121.60, 121.16, 112.81, 112.56,108.63. HRMS (ESI+): Calcd for C₉H₉N₃O [M+H]⁺: 176.1592, Found:176.0813.

N′-hydroxy-1H-indole-4-carboximidamide (2b)

2b was prepared using general procedure 1. Purification on a silica gelcolumn with 70-100% ethyl acetate in hexanes produced 2b as a mixture ofenantiomers (1.12 g, 91%), a tan solid. ¹H NMR (500 MHz, CD₃OD) δ 7.45(dd, J=8.1, 1.6 Hz, 1H), 7.28 (dd, J=3.4, 1.8 Hz, 1H), 7.24 (dd, J=7.2,1.6 Hz, 1H), 7.13 (td, J=7.8, 1.8 Hz, 1H), 6.78 (dd, J=3.0, 1.8 Hz, 1H).¹³C NMR (126 MHz, CD₃OD) δ 156.61, 138.10, 127.13, 126.30, 125.70,121.84, 119.25, 113.79, 102.54. HRMS (ESI+): Calcd for C₉H₉N₃O [M+H]⁺:176.1592, Found: 176.0825.

N′-hydroxy-1H-indole-5-carboximidamide (2c)

2c was prepared using general procedure 1. Purification on a silica gelcolumn with 70-100% ethyl acetate in hexanes produced 2c as a mixture ofenantiomers (1.78 g, 96%), a tan solid. ¹H NMR (400 MHz, CD₃OD) δ 7.88(dd, J=1.6, 0.8 Hz, 1H), 7.43-7.37 (m, 2H), 7.25 (d, J=3.2 Hz, 1H), 6.49(dd, J=3.2, 0.8 Hz, 1H). ¹³C NMR (101 MHz, CD₃OD) δ 157.16, 137.03,130.71, 128.86, 127.55, 127.38, 126.62, 121.11, 120.89, 119.19, 118.35,112.59, 110.45, 102.60, 102.41. HRMS (ESI+): Calcd for C₉H₉N₃O [M+H]⁺:176.1592, Found: 176.0812.

N′-hydroxy-1H-indole-6-carboximidamide (2d)

2d was prepared using general procedure 1. Purification on a silica gelcolumn with 70-100% ethyl acetate in hexanes produced 2d as a mixture ofenantiomers (1.12 g, 91%), a tan solid. ¹H NMR (400 MHz, CD₃OD) δ 8.03(dt, J=1.7, 0.9 Hz, 0.1H), 7.72 (dt, J=1.7, 0.8 Hz, 1H), 7.61-7.54 (m,1H), 7.34 (dd, J=8.3, 1.6 Hz, 1H), 7.27 (d, J=3.2 Hz, 1H), 6.50 (dd,J=3.1, 1.0 Hz, 0.1H), 6.46 (dd, J=3.1, 1.0 Hz, 1H). ¹³C NMR (101 MHz,CD₃OD) δ 157.16, 137.03, 130.71, 128.86, 127.55, 127.38, 126.62, 121.11,120.89, 119.19, 118.35, 112.59, 110.50, 110.45, 102.60, 102.46, 102.41.HRMS (ESI+): Calcd for C₉H₉N₃O [M+H]⁺: 176.1592, Found: 176.0812.

Tert-butyl(S)-2-(3-(1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(3a)

3a was prepared using general procedure 2. Purification on a silica gelcolumn with 20-40% ethyl acetate in hexanes produced 3a (100 mg, 5%), alight yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.29 (s, 1H), 8.28-8.10(m, 1H), 7.91 (d, J=2.8 Hz, 1H), 7.45-7.36 (m, 1H), 7.32-7.13 (m, 2H),5.17 (ddd, J=78.1, 8.5, 3.5 Hz, 1H), 3.76-3.68 (m, 1H), 3.64-3.47 (m,1H), 2.43-2.30 (m, 1H), 2.24-2.12 (m, 1H), 2.05-1.95 (m, 1H), 1.41 (d,J=82.0 Hz, 8H). ¹³C NMR (101 MHz, CDCl₃) δ 179.25, 165.41, 154.04,136.77, 128.73, 127.54, 124.91, 123.31, 122.96, 121.76, 121.56, 121.27,111.71, 104.43, 80.77, 60.54, 53.95, 46.97, 46.50, 32.46, 31.60, 28.60,28.29, 24.50, 23.79, 14.30. HRMS (ESI+): Calcd for C₁₉H₂₂N₄O₃ [M+Na]⁺:377.3927, Found: 377.1582.

Tert-butyl(S)-2-(3-(1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(3b)

3b was prepared using general procedure 2. Purification on a silica gelcolumn with 20-35% ethyl acetate in hexanes produced 3b (0.65 g, 32%), atan solid. ¹H NMR (400 MHz, CDCl₃) δ 9.31-9.16 (m, 1H), 7.98-7.85 (m,1H), 7.80-7.72 (m, 1H), 7.56-7.47 (m, 1H), 7.36-7.27 (m, 1H), 7.25-7.16(m, 1H), 5.31-5.12 (m, 1H), 3.80-3.68 (m, 1H), 3.60-3.47 (m, 1H),2.44-2.30 (m, 1H), 2.24-2.11 (m, 2H), 2.07-1.94 (m, 1H), 1.46-1.20 (m,9H). HRMS (ESI+): Calcd for C₁₉H₂₂N₄O₃ [M+Na]t 377.3927, Found:377.1587.

Tert-butyl(S)-2-(3-(1H-indol-5-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(3c)

3c was prepared using general procedure 2. Purification on a silica gelcolumn with 20-40% ethyl acetate in hexanes produced 3c (0.47 g, 16%), atan solid. ¹H NMR (400 MHz, CDCl₃) δ 8.45-8.28 (m, 1H), 7.94-7.77 (m,1H), 7.44 (dd, J=31.5, 8.7 Hz, 1H), 7.34-7.23 (m, 1H), 6.66-6.51 (m,1H), 5.16 (ddd, J=59.4, 8.7, 3.2 Hz, 1H), 3.78-3.64 (m, 1H), 3.62-3.43(m, 1H), 2.48-2.31 (m, 1H), 2.25-2.10 (m, 2H), 2.05-1.94 (m, 1H), 1.39(d, J=67.9 Hz, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 180.08, 179.56, 169.46,154.53, 153.90, 137.62, 127.97, 125.85, 125.64, 120.89, 120.77, 117.92,111.77, 111.61, 103.09, 80.72, 80.55, 77.48, 77.16, 76.84, 53.90, 46.75,46.44, 38.65, 32.36, 31.52, 28.43, 28.17, 24.33, 23.70. HRMS (ESI+):Calcd for C₁₉H₂₂N₄O₃ [M+Na]⁺: 377.3927, Found: 377.1589.

Tert-butyl(S)-2-(3-(1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(3d)

3d was prepared using general procedure 2. Purification on a silica gelcolumn with 20-50% ethyl acetate in hexanes produced 3d (0.57 g, 28%), atan solid. ¹H NMR (500 MHz, CDCl₃) δ 8.85 (s, 1H), 8.13 (d, J=50.4 Hz,1H), 7.88-7.64 (m, 2H), 7.38-7.28 (m, 1H), 6.65-6.54 (m, 1H), 5.17 (ddd,J=75.7, 8.4, 3.3 Hz, 1H), 3.81-3.66 (m, 1H), 3.62-3.46 (m, 1H),2.48-2.31 (m, 1H), 2.22-2.13 (m, 2H), 2.07-1.93 (m, 1H), 1.40 (d, J=87.4Hz, 10H). ¹³C NMR (126 MHz, CDCl₃) δ 180.27, 169.42, 153.99, 135.72,130.38, 126.81, 121.20, 120.16, 118.92, 111.12, 103.01, 80.84, 54.03,46.54, 32.47, 28.55, 28.29, 23.81. HRMS (ESI+): Calcd for C₁₉H₂₂N₄O₃[M+H]: 377.3927, Found: 377.1600.

Tert-butyl(S)-2-(3-(1-heptyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4e)

4e was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4e (34 mg, 89%), ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.30-8.21 (m, 1H), 7.83 (s, 1H),7.42-7.36 (m, 1H), 7.35-7.26 (m, 2H), 5.26-5.04 (m, 1H), 4.16 (q, J=6.4,5.7 Hz, 2H), 3.75 (ddd, J=10.6, 7.4, 5.0 Hz, 1H), 3.57 (dt, J=10.6, 7.0Hz, 1H), 2.40 (tt, J=10.7, 6.0 Hz, 1H), 2.23-2.11 (m, 2H), 2.01 (ddt,J=9.6, 6.9, 3.6 Hz, 1H), 1.88 (q, J=7.0 Hz, 2H), 1.51-1.18 (m, 17H),0.93-0.83 (m, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 179.20, 165.27, 153.81,136.91, 130.58, 125.63, 122.87, 122.73, 122.13, 121.33, 121.22, 110.01,102.92, 80.52, 77.48, 77.16, 76.84, 53.93, 47.03, 46.77, 46.47, 32.54,31.77, 31.63, 30.13, 28.99, 28.55, 28.29, 27.01, 24.50, 23.84, 22.68,14.17. HRMS (ESI+): Calcd for C₂₆H₃₆N₄O₃ [M+K]⁺: 491.6873, Found:491.2428.

Tert-butyl(S)-2-(3-(1-octyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4f)

4f was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4f (15 mg, 9%), ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 1H NMR (400 MHz, Chloroform-d) δ8.29-8.18 (m, 1H), 7.83 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.36-7.23 (m,3H), 5.27-5.03 (m, 1H), 4.17 (t, J=7.1 Hz, 2H), 3.77-3.65 (m, 1H),3.62-3.49 (m, 1H), 2.47-2.31 (m, 1H), 2.22-2.11 (m, 2H), 2.03-1.97 (m,1H), 1.91-1.85 (m, 2H), 1.52-1.16 (m, 18H), 0.93-0.78 (m, 3H). HRMS(ESI+): Calcd for C₂₇H₃₈N₄O₃ [M+K]: 505.7139, Found: 505.2567.

Tert-butyl(S)-2-(3-(1-nontyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4g)

4g was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4g (40 mg, 74%), ayellow oil. ¹¹H NMR (400 MHz, CDCl₃) 8.31-8.20 (m, 1H), 7.83 (s, 1H),7.44-7.35 (m, 1H), 7.35-7.21 (m, 2H), 5.23-5.03 (m, 1H), 4.16 (t, J=7.1Hz, 2H), 3.81-3.63 (m, 1H), 3.61-3.50 (m, 1H), 2.45-2.31 (m, 1H),2.26-2.09 (m, 2H), 2.05-195 (m, 1H), 1.89 (p, J=7.0 Hz, 2H), 1.52-1.19(m, 19H), 0.87 (t, J=7.0 Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ 179.19,165.27, 153.80, 136.91, 130.57, 125.63, 122.86, 122.72, 122.13, 121.32,110.00, 102.93, 80.50, 53.93, 47.02, 46.47, 32.53, 31.92, 31.62, 30.12,29.52, 29.32, 28.54, 28.28, 27.04, 24.49, 23.83, 22.75, 22.74, 14.21.HRMS (ESI+): Calcd for C₂₈H₄₀N₄O₃ [M+K]⁺: 519.7405, Found: 519.2736.

Tert-butyl(S)-2-(3-(1-decyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4h)

4h was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4h (42 mg, 100%), ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.26-8.20 (m, 1H), 7.84 (s, 1H),7.44-7.35 (m, 1H), 7.35-7.24 (m, 2H), 5.24-5.04 (m, 1H), 4.16 (t, J=7.0Hz, 2H), 3.75 (m, 1H), 3.61-3.52 (m, 1H), 2.46-2.31 (m, 1H), 2.26-2.12(m, 2H), 2.07-1.94 (m, 1H), 1.93-1.83 (m, 2H), 1.50-1.20 (m, 22H), 0.87(t, J=7.0 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 179.19, 165.26, 153.80,136.90, 130.57, 125.62, 122.86, 122.72, 122.12, 121.32, 121.20, 110.00,102.91, 80.51, 53.92, 47.03, 46.76, 46.46, 32.53, 31.96, 31.62, 30.12,29.61, 29.56, 29.38, 29.33, 28.54, 28.28, 27.04, 24.49, 23.83, 22.78,14.23. HRMS (ESI+): Calcd for C₂₉H₄₂N₄O₃ [M+K]⁺: 533.7616, Found:533.2902.

Tert-butyl(S)-2-(3-(1-undecyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4i)

4i was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4i (22 mg, 77%), ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (dd, J=6.9, 2.0 Hz, 1H), 7.83(s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.28 (d, J=14.4 Hz, 2H), 5.23-5.06 (m,1H), 4.16 (t, J=7.1 Hz, 2H), 3.75 (dt, J=12.1, 6.0 Hz, 1H), 3.57 (dt,J=10.4, 7.0 Hz, 1H), 2.45-2.29 (m, 1H), 2.24-2.10 (m, 2H), 2.06-1.98 (m,1H), 1.89 (t, J=7.1 Hz, 2H), 1.53-1.14 (m, 24H), 0.94-0.82 (m, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 179.21, 165.31, 153.83, 136.95, 130.57, 125.69,122.88, 122.17, 121.34, 110.00, 103.00, 80.52, 53.96, 47.05, 46.49,32.56, 32.03, 30.16, 29.69, 29.59, 29.43, 29.36, 28.57, 28.31, 27.08,23.85, 22.81, 14.25. HRMS (ESI+): Calcd for C₃₀H₄₄N₄O₃ [M+Na]⁺:531.6851, Found: 531.3354.

Tert-butyl(S)-2-(3-(1-dodecyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4j)

4j was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4j (26 mg, 59%), ayellow oil. ¹H NMR (400 MHz, CDCl₃) 1H NMR (400 MHz, Chloroform-d) δ8.24 (d, J=7.3 Hz, 1H), 7.83 (s, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.26 (s,2H), 5.29-5.05 (m, 1H), 4.17 (t, J=7.0 Hz, 2H), 3.81-3.67 (m, 1H),3.61-3.47 (m, 1H), 2.46-2.30 (m, 1H), 2.21-2.12 (m, 1H), 2.05 (s, 1H),1.88 (d, J=7.1 Hz, 2H), 1.49-1.20 (m, 17H), 0.92-0.77 (m, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 179.21, 165.30, 145.25, 136.93, 130.60, 125.67,122.88, 122.17, 121.35, 110.02, 102.96, 80.54, 53.96, 47.07, 46.50,32.57, 32.05, 30.16, 29.74, 29.60, 29.48, 29.37, 28.31, 27.09, 23.86,22.83, 14.28. HRMS (ESI+): Calcd for C₃₁H₄₆N₄O₃ [M+Na]⁺: 545.7117,Found: 545.3447.

Tert-butyl(S)-2-(3-(1-heptyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4k)

4k was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4k (22 mg, 57%), ayellow oil. ¹H NMR (500 MHz, solvent) δ 7.97-7.91 (m, 1H), 7.50 (d,J=8.2 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.26-7.22 (m, 1H), 7.20 (d, J=3.1Hz, 1H), 5.30-5.08 (m, 1H), 4.17 (t, J=7.0 Hz, 2H), 3.77-3.61 (m, 1H),3.61-3.48 (m, 1H), 2.44-2.35 (m, 1H), 2.24-2.13 (m, 2H), 2.05-1.95 (m,1H), 1.85 (p, J=8.0, 7.2 Hz, 2H), 1.48-1.20 (m, 19H), 0.86 (t, J=6.9 Hz,4H). ¹³C NMR (126 MI-lz, CDCl₃) δ 179.70, 169.01, 153.81, 136.65,129.53, 126.32, 121.19, 120.78, 118.50, 112.63, 102.48, 80.57, 54.02,46.75, 46.50, 32.59, 31.83, 30.50, 29.04, 28.58, 28.33, 27.09, 23.85,22.70, 14.17. HRMS (ESI+): Calcd for C₂₆H₃₆N₄O₃ [M+Na]⁺: 475.5788,Found: 475.2673.

Tert-butyl(S)-2-(3-(1-octyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4l)

4l was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4l (30 mg, 76%), ayellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.86 (d, J=7.3 Hz, 1H), 7.43 (d,J=8.2 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.17 (d, J=3.2 Hz, 1H), 7.12 (d,J=3.2 Hz, 1H), 5.22-5.01 (m, 1H), 4.09 (t, J=7.0 Hz, 2H), 3.72-3.58 (m,1H), 3.54-3.45 (m, 1H), 2.40-2.24 (m, 1H), 2.17-2.06 (m, 2H), 1.99-1.89(m, 1H), 1.78 (p, J=7.0 Hz, 2H), 1.40 (s, 2H), 1.28-1.12 (m, 19H), 0.79(t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 179.70, 169.00, 153.81,136.64, 129.53, 126.32, 121.18, 120.78, 118.50, 112.63, 102.47, 80.56,54.02, 46.75, 46.50, 32.59, 31.89, 30.49, 29.33, 29.28, 28.57, 28.32,27.12, 23.85, 22.74, 14.26, 14.19. HRMS (ESI+): Calcd for C₂₇H₃₈N₄O₃[M+Na]⁺: 489.6054, Found: 489.2820.

Tert-butyl(S)-2-(3-(1-nonyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4m)

4m was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4m (29 mg, 71%), ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (dd, J=7.4, 0.9 Hz, 1H), 7.50(d, J=8.3 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.26-7.23 (m, 1H), 7.20 (d,J=3.0 Hz, 1H), 5.31-5.10 (m, 1H), 4.16 (t, J=7.1 Hz, 2H), 3.81-3.68 (m,1H), 3.62-3.49 (m, 1H), 2.47-2.34 (m, 1H), 2.26-2.13 (m, 2H), 2.06-1.96(m, 1H), 1.86 (p, J=7.2 Hz, 2H), 1.52-1.19 (m, 19H), 0.87 (t, J=7.0 Hz,3H). ¹³C NMR (101 MHz, CDCl₃) δ 179.66, 168.95, 153.76, 136.57, 129.52,126.25, 121.14, 120.73, 118.42, 112.62, 102.40, 80.51, 53.97, 46.70,46.46, 32.55, 31.91, 30.45, 29.54, 29.33, 29.31, 28.53, 28.28, 27.07,23.81, 22.74, 14.20. HRMS (ESI+): Calcd for C₂₈H₄₀N₄O₃ [M+Na]t 503.6320,Found: 503.2987.

Tert-butyl(S)-2-(3-(1-decyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4n)

4n was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4n (30 mg, 72%), ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (dd, J=7.4, 0.9 Hz, 1H), 7.50(d, J=8.3 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.25 (d, J=3.2 Hz, 1H), 7.20(d, J=3.1 Hz, 1H), 5.30-5.09 (m, 1H), 4.16 (t, J=7.1 Hz, 2H), 3.78-3.62(m, 1H), 3.60-3.52 (m, 1H), 2.44-2.31 (m, 1H), 2.24-2.11 (m, 2H),2.05-1.94 (m, 1H), 1.85 (p, J=7.0 Hz, 2H), 1.51-1.21 (m, 21H), 0.87 (t,J=7.0 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 179.67, 168.97, 153.78,136.59, 129.54, 126.26, 121.16, 121.06, 120.75, 118.44, 112.63, 102.42,80.53, 53.99, 46.73, 46.48, 32.57, 31.97, 30.47, 29.62, 29.60, 29.38,29.35, 28.55, 28.30, 27.09, 23.83, 22.78, 14.24. HRMS (ESI+): Calcd forC₂₉H₄₂N₄O₃ [M+Na]⁻: 517.6585, Found: 517.3177.

Tert-butyl(S)-2-(3-(1-nonyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4r)

4r was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4r (28 mg, 52%), ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J=1.6 Hz, 1H), 7.92 (dd,J=8.6, 1.6 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.15 (d, J=3.1 Hz, 1H), 6.57(d, J=3.2 Hz, 1H), 5.26-5.04 (m, 1H), 4.13 (t, J=7.2 Hz, 2H), 3.79-3.66(m, 1H), 3.57 (dt, J=10.5, 7.0 Hz, 1H), 2.45-2.33 (m, 1H), 2.17 (ddd,J=18.7, 14.1, 6.7 Hz, 2H), 2.01 (ddd, J=12.1, 6.1, 3.4 Hz, 1H),1.90-1.80 (m, 2H), 1.57-1.12 (m, 20H), 0.97-0.78 (m, 3H). ¹³C NMR (101MHz, CDCl₃) δ 169.51, 153.78, 137.61, 129.13, 128.67, 121.33, 120.68,117.90, 109.91, 102.25, 80.53, 77.48, 77.16, 76.84, 54.02, 46.73, 46.50,32.55, 31.94, 30.41, 29.56, 29.35, 29.33, 28.56, 28.30, 27.09, 23.85,22.76, 14.21. HRMS (ESI+): Calcd for C₂₈H₄₀N₄O₃ [M+Na]⁺: 503.6320,Found: 503.2966.

Tert-butyl(S)-2-(3-(1-octyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4u)

4u was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4u (51 mg, 97%), ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=1.2 Hz, 1H), 7.88-7.77(m, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.21 (t, J=3.6 Hz, 1H), 6.53 (d, J=3.2Hz, 1H), 5.24-5.06 (m, 1H), 4.18 (t, J=7.1 Hz, 2H), 3.81-3.69 (m, 1H),3.58 (dt, J=10.3, 7.0 Hz, 1H), 2.48-2.32 (m, 1H), 2.28-2.13 (m, 2H),2.07-1.96 (m, 1H), 1.86 (t, J=7.2 Hz, 2H), 1.49-1.19 (m, 17H), 0.91-0.82(m, 3H). ¹³C NMR (101 MHz, solvent) δ 180.26, 169.55, 153.77, 135.86,130.99, 130.21, 121.40, 119.69, 118.48, 109.24, 101.50, 80.56, 77.48,77.16, 76.84, 54.02, 46.70, 46.50, 32.55, 31.88, 30.47, 29.33, 29.28,28.53, 28.28, 27.10, 23.88, 22.72, 14.19. HRMS (ESI+): Calcd forC₂₇H₃₈N₄O₃ [M+Na]⁺: 489.6054, Found: 489.2836.

Tert-butyl(S)-2-(3-(1-decyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4w)

4w was prepared using general procedure 3. Purification on a silica gelcolumn with 0-20% ethyl acetate in hexanes produced 4w (92 mg, 94%), ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.83 (d, J=8.1 Hz,1H), 7.69 (d, J=8.4 Hz, 1H), 7.21 (d, J=3.1 Hz, 1H), 6.53 (d, J=3.1 Hz,1H), 5.26-5.07 (m, 1H), 4.18 (t, J=7.1 Hz, 2H), 3.82-3.68 (m, 1H),3.63-3.50 (m, 1H), 2.48-2.32 (m, 1H), 2.25-2.13 (m, 2H), 2.07-1.97 (m,1H), 1.85 (p, J=7.1 Hz, 2H), 1.47 (s, 3H), 1.37-1.19 (m, 19H), 0.87 (t,J=7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 180.25, 169.52, 153.75,135.83, 130.98, 130.21, 130.05, 121.38, 121.24, 119.66, 118.58, 118.45,109.37, 109.22, 101.48, 101.41, 80.53, 54.00, 46.76, 46.68, 46.49,32.53, 31.96, 31.66, 30.46, 29.61, 29.60, 29.55, 29.37, 29.36, 28.51,28.27, 27.08, 24.48, 23.86, 22.77, 14.22. HRMS (ESI+): Calcd forC₂₉H₄₂N₄O₃ [M+Na]⁺: 517.6585, Found: 517.3124.

(S)-2-(3-(1-heptyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5e)

5e was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-octyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5f)

5f was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-nonyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5g)

5g was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-decyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5h)

5h was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-undecyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5i)

5i was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-dodecyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5j)

5j was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-heptyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5k)

5k was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-octyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5l)

5l was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-nonyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5m)

5m was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-decyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5n)

5n was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-nonyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5r)

5r was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-octyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5u)

5u was prepared using general procedure 4 and carried on to the nextreaction without purification.

(S)-2-(3-(1-decyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5w)

5w was prepared using general procedure 4 and carried on to the nextreaction without purification.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)imino)(2-(3-(1-hexyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)carbamate(6e)

6e was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 6e (21 mg, 53%), aclear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.20-8.05 (m, 1H), 7.77 (s, 1H),7.40-7.30 (m, 1H), 7.27-7.12 (m, 2H), 5.52 (s, 1H), 4.09 (t, J=7.2 Hz,2H), 3.83 (ddd, J=11.5, 7.5, 6.0 Hz, 1H), 3.73 (d, J=9.9 Hz, 1H), 2.38(dq, J=12.7, 7.7 Hz, 1H), 2.22 (s, 1H), 2.16-2.07 (m, 1H), 2.01-1.92 (m,1H), 1.81 (t, J=7.3 Hz, 2H), 1.42 (d, J=18.3 Hz, 19H), 1.29-1.04 (m,9H), 0.79 (t, J=6.9 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 177.45, 165.30,161.89, 153.52, 151.07, 136.94, 130.79, 125.64, 122.85, 122.13, 121.35,109.98, 102.77, 81.77, 79.82, 76.91, 55.43, 49.54, 47.06, 36.78, 31.77,31.51, 30.20, 29.01, 28.26, 28.12, 27.03, 22.69, 14.15. HRMS (ESI+):Calcd for C₃₂H₄₆N₆O₅ [M+H]⁺: 595.7528, Found: 595.3608.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)imino)(2-(3-(1-octcyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)carbamate(6f)

6f was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 6f (15 mg, 76%), aclear oil. ¹H NMR (500 MHz, CDCl) δ 8.27-8.18 (m, 1H), 7.83 (s, 1H),7.42-7.36 (m, 1H), 7.32-7.25 (m, 2H), 5.59 (d, J=6.4 Hz, 1H), 4.16 (t,J=7.2 Hz, 2H), 3.93-3.88 (m, 1H), 3.82 (q, J=6.0, 4.9 Hz, 1H), 2.51-2.41(m, 1H), 2.29 (s, 1H), 2.17-2.11 (m, 1H), 2.04 (dt, J=12.7, 6.4 Hz, 1H),1.89 (p, J=7.1 Hz, 2H), 1.49 (d, J=19.9 Hz, 21H), 1.35-1.21 (m, 10H),0.87 (t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 177.46, 165.36,161.98, 153.46, 150.70, 137.00, 130.75, 125.71, 122.87, 122.18, 121.37,109.98, 102.88, 81.69, 79.82, 55.48, 49.57, 47.08, 31.90, 31.52, 30.22,29.33, 29.24, 28.29, 28.14, 27.71, 27.09, 24.00, 22.73, 14.18. HRMS(ESI+): Calcd for C₃₃H₄₈N₆O₅ [M+H]⁺: 609.7794, Found: 609.3371.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)imino)(2-(3-(1-nonyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrodinyl-1-yl)methyl)carbamate(6g)

6g was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 6g (25 mg, 64%), aclear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.31-8.19 (m, 1H), 7.86 (s, 1H),7.46-7.41 (m, 1H), 7.37-7.28 (m, 2H), 5.61 (s, 1H), 4.18 (t, J=7.2 Hz,2H), 3.94-3.88 (m, 1H), 3.85-3.79 (m, 1H), 2.51-2.45 (m, 1H), 2.36-2.26(m, 1H), 2.24-2.15 (m, 1H), 2.08-1.98 (m, 1H), 1.90 (p, J=7.4 Hz, 3H),1.64-1.43 (m, 18H), 1.40-1.32 (m, 4H) 1.32-1.21 (m, 8H), 0.89 (t, J=6.9Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 177.46, 165.30, 162.05, 153.60,150.56, 136.94, 130.78, 125.64, 122.84, 122.13, 121.35, 109.98, 102.78,82.24, 79.67, 55.42, 49.53, 47.06, 31.93, 31.53, 31.37, 30.20, 29.52,29.35, 28.26, 28.12, 27.07, 22.75, 14.21. HRMS (ESI+): Calcd forC₃₄H₅₀N₆O₅ [M+H]⁺: 623.8059, Found: 623.3915.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)imino)(2-(3-(1-decyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)carbamate(6h)

6h was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 6h (23 mg, 52%), aclear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.17-8.12 (m, 1H), 7.77 (s, 1H),7.34-7.28 (m, 1H), 7.26-7.20 (m, 2H), 5.52 (s, 1H), 4.09 (t, J=7.2 Hz,2H), 3.86-3.79 (m, 1H), 3.76-3.68 (m, 1H), 2.39-2.34 (m, 1H), 2.29-2.17(m, 1H), 2.16-2.06 (m, 1H), 2.01-1.92 (m, 1H), 1.81 (p, J=7.4 Hz, 2H),1.48-1.32 (m, 22H), 1.27-1.23 (m, 4H), 1.18 (d, J=14.9 Hz, 10H), 0.80(t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 177.46, 165.30, 162.12,153.53, 150.94, 136.94, 130.79, 125.64, 122.84, 122.13, 121.35, 109.98,102.78, 82.17, 79.82, 55.42, 49.53, 47.07, 31.97, 31.53, 31.37, 30.21,29.64, 29.57, 29.37, 28.27, 28.12, 27.98, 27.07, 22.79, 14.23. HRMS(ESI+): Calcd for C₃₅H₅₂N₆O₅ [M+H]⁺: 637.8325, Found: 637.4073.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)imino)(2-(3-(1-undecyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)carbamate(6i)

6i was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 61 (21 mg, 100%), aclear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.26-8.19 (m, 1H), 7.83 (s, 1H),7.44-7.36 (m, 1H), 7.33-7.26 (m, 2H), 4.16 (t, J=7.2 Hz, 2H), 3.97-3.88(m, 1H), 3.81 (d, J=10.4 Hz, 1H), 2.51-2.42 (m, 1H), 2.29 (s, 1H), 2.18(dd, J=13.1, 6.8 Hz, 1H), 2.04 (dp, J=13.0, 6.6 Hz, 1H), 1.89 (t, J=7.2Hz, 2H), 1.68-1.41 (m, 19H), 1.38-1.12 (m, 18H), 0.87 (t, J=7.0 Hz, 3H).¹³C NMR (126 MHz, CDCl₃) δ 177.43, 165.33, 161.84, 153.32, 150.29,136.96, 130.78, 125.66, 122.86, 122.16, 121.37, 109.99, 102.81, 82.20,79.73, 55.48, 49.58, 47.09, 32.03, 31.53, 30.23, 29.70, 29.59, 29.41,28.28, 27.10, 24.05, 22.82, 14.26. HRMS (ESI+): Calcd for C₃₆H₅₄N₆O₅[M+H]⁺: 651.8591, Found: 651.4249.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)imino)(2-(3-(1-dodecyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)carbamate(6j)

6j was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 6j (21 mg, 99%), aclear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.26-8.18 (m, 1H), 7.83 (s, 1H),7.45-7.35 (m, 1H), 7.32-7.26 (m, 2H), 5.58 (s, 1H), 4.16 (t, J=7.2 Hz,2H), 3.89 (ddd, J=11.6, 7.5, 5.9 Hz, 1H), 3.81 (s, 1H), 2.43 (d, J=7.6Hz, 1H), 2.18 (dq, J=13.7, 6.8 Hz, 1H), 2.05 (d, J=6.4 Hz, 1H), 1.88 (t,J=7.2 Hz, 2H), 1.59-1.18 (m, 38H), 0.87 (t, J=7.0 Hz, 3H). ¹³C NMR (126MHz, CDCl₃) δ 177.46, 165.31, 162.06, 150.60, 148.74, 136.93, 130.78,125.63, 122.84, 122.13, 121.35, 109.98, 102.78, 82.23, 79.66, 77.73,77.41, 77.36, 77.16, 76.91, 55.42, 49.53, 47.07, 32.04, 31.52, 30.21,29.84, 29.73, 29.70, 29.62, 29.58, 29.46, 29.38, 28.27, 28.12, 27.09,22.82, 14.26. HRMS (ESI+): Calcd for C₃₇H₅₆N₆O₅ [M+H]⁺: 665.8857, Found:665.4401.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(1-heptyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6k)

6k was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 6k (13 mg, 43%), aclear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (dd, J=7.4, 0.9 Hz, 1H),7.54-7.47 (m, 1H), 7.32-7.27 (m, 1H), 7.23 (t, J=1.6 Hz, 1H), 7.18 (dd,J=3.1, 0.8 Hz, 1H), 5.64 (t, J=6.2 Hz, 1H), 4.17 (t, J=7.1 Hz, 2H),3.95-3.87 (m, 1H), 3.86-3.76 (m, 1H), 2.52-2.41 (m, 1H), 2.37-2.26 (m,1H), 2.25-2.13 (m, 2H), 2.10-1.99 (m, 1H), 1.86 (p, J=7.1 Hz, 2H),1.53-1.39 (m, 17H), 1.35-1.29 (d, J=5.2 Hz, 4H), 1.29-1.20 (m, 6H), 0.86(t, J=6.9 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 177.97, 169.01, 162.19,153.75, 150.66, 136.64, 129.53, 129.44, 126.30, 121.10, 120.96, 118.32,112.67, 102.52, 81.88, 79.71, 55.48, 49.55, 46.75, 31.83, 31.56, 30.50,29.84, 29.04, 28.28, 27.08, 24.07, 22.71, 14.18. HRMS (ESI+): Calcd forC₃₂H₄₆N₆O₅ [M+Na]⁺:617.7346, Found: 617.3426.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(1-heptyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6l)

6l was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 61 (7 mg, 15%), aclear oil. ¹H NMR (500 MHz, CDCl₃) δ 7.93 (dd, J=7.5, 0.9 Hz, 1H), 7.49(d, J=8.2 Hz, 1H), 7.28 (dd, J=8.2, 7.4 Hz, 1H), 7.24-7.22 (m, 1H), 7.18(dd, J=3.1, 0.9 Hz, 1H), 5.65 (s, 1H), 4.17 (t, J=7.1 Hz, 2H), 3.94-3.87(m, 1H), 3.87-3.77 (m, 1H), 2.50-2.42 (m, 1H), 2.35-2.26 (m, 1H), 2.20(dt, J=13.7, 6.7 Hz, 1H), 2.10-2.01 (m, 1H), 1.85 (p, J=7.5 Hz, 2H),1.51-1.38 (m, 20H), 1.33-1.29 (m, 4H), 1.28-1.20 (m, 8H), 0.86 (t, J=7.0Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 177.97, 169.02, 162.12, 153.64,150.64, 136.65, 129.50, 126.32, 121.11, 120.96, 118.35, 112.67, 102.53,82.22, 79.80, 55.49, 49.55, 46.75, 31.90, 31.54, 30.50, 29.84, 29.32,28.28, 27.13, 24.04, 22.75, 14.20. HRMS (ESI+): Calcd for C₃₃H₄₈N₆O₅[M+H]⁻: 609.7794, Found: 609.3785.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(1-heptyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6m)

6m was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 6m (20 mg, 45%), aclear oil. ¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J=7.3 Hz, 1H), 7.49 (d,J=8.2 Hz, 1H), 7.33-7.26 (m, 2H), 7.24-7.22 (m, 1H), 7.18 (d, J=3.1 Hz,1H), 5.65 (s, 1H), 4.16 (t, J=7.1 Hz, 2H), 3.95-3.90 (m, 1H), 3.84-3.78(m, 1H), 2.52-2.46 (m, 1H), 2.22-2.18 (m, 1H), 2.11-2.03 (m, 1H), 1.85(p, J=7.2 Hz, 2H), 1.56-1.34 (m, 21H), 1.33-1.28 (m, 4H), 1.27-1.18 (m,10H), 0.86 (t, J=6.9 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 177.95, 169.00,162.07, 153.64, 150.64, 136.64, 129.52, 126.33, 121.10, 120.96, 118.32,112.67, 102.52, 82.29, 79.76, 55.48, 49.54, 46.75, 31.96, 31.57, 30.49,29.85, 29.58, 29.38, 29.35, 28.28, 28.14, 27.12, 24.05, 22.77, 14.23.HRMS (ESI+): Calcd for C₃₄H₅₀N₆O₅ [M+H]⁺: 623.8059, Found: 623.3915.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(1-heptyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6n)

6n was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 6n (10 mg, 34%), aclear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (dd, J=7.4, 0.9 Hz, 1H), 7.49(d, J=8.2 Hz, 1H), 7.28 (dd, J=8.2, 7.4 Hz, 1H), 7.24-7.22 (m, 1H), 7.18(dd, J=3.1, 0.8 Hz, 1H), 5.64 (s, 1H), 4.16 (t, J=7.1 Hz, 2H), 3.96-3.87(m, 1H), 3.86-3.76 (m, 1H), 2.51-2.41 (m, 1H), 2.30 (s, 1H), 2.24-2.13(m, 1H), 2.10-2.00 (m, 1H), 1.85 (p, J=7.0 Hz, 2H), 1.53-1.38 (m, 21H),1.35-1.28 (m, 6H), 1.28-1.19 (m, 12H), 0.86 (t, J=7.1 Hz, 3H). ¹³C NMR(126 MHz, CDCl₃) δ 177.95, 169.01, 162.08, 153.49, 150.61, 136.64,129.52, 129.43, 126.32, 121.10, 120.96, 118.32, 112.67, 102.52, 82.28,79.69, 55.48, 49.54, 46.75, 31.99, 31.56, 30.49, 29.85, 29.63, 29.39,28.28, 27.12, 24.02, 22.80, 14.24. HRMS (ESI+): Calcd for C₃₅H₅₂N₆O₅[M+H]⁺: 637.8325, Found: 637.4083.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)imino)(2-(3-(1-nonyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)carbamate(6r)

6r was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 6r (11 mg, 41%), aclear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.37 (d, J=1.5 Hz, 1H), 7.91 (dd,J=8.6, 1.6 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.14 (t, J=1.6 Hz, 1H), 6.56(dd, J=3.1, 0.8 Hz, 0H), 5.59 (dd, J=7.9, 4.6 Hz, 1H), 4.13 (t, J=7.2Hz, 2H), 3.94-3.89 (m, 1H), 3.84-3.78 (m, 1H), 2.50-2.42 (m, 1H), 2.30(s, 1H), 2.17 (dd, J=8.1, 6.0 Hz, 1H), 2.09-2.01 (m, 1H), 1.86-1.79 (m,2H), 1.49 (d, J=18.9 Hz, 20H), 1.37-1.17 (m, 14H), 0.86 (t, J=6.9 Hz,3H). ¹³C NMR (126 MHz, CDCl₃) δ 178.35, 169.51, 153.46, 137.65, 129.05,128.61, 121.49, 120.75, 117.69, 109.87, 102.28, 81.06, 77.41, 77.16,76.91, 55.50, 49.61, 46.75, 31.95, 31.48, 30.43, 29.85, 29.58, 29.36,28.27, 27.99, 27.11, 24.06, 22.78, 14.23. HRMS (ESI+): Calcd forC₃₄H₅₀N₆O₅ [M+Na]⁺: 645.7878, Found: 645.3714.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)imino)(2-(3-(1-octyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)carbamate(6u)

6u was prepared using general procedure 5. Purification on a silica gelcolumn with 10-40% ethyl acetate in hexanes produced 6u (33 mg, 55%), aclear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.08 (s, 1H), 7.81 (dd, J=8.3, 1.4Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.20 (d, J=3.1 Hz, 1H), 6.52 (d, J=3.0Hz, 1H), 5.62 (dd, J=7.8, 4.7 Hz, 1H), 4.17 (t, J=7.2 Hz, 2H), 3.92 (dt,J=11.4, 6.9 Hz, 1H), 3.82 (d, J=12.7 Hz, 1H), 2.46 (dd, J=13.1, 7.0 Hz,1H), 2.34-2.12 (m, 2H), 2.04 (dt, J=12.8, 6.6 Hz, 1H), 1.85 (q, J=7.0Hz, 2H), 1.68-1.15 (m, 28H), 0.86 (t, J=6.8 Hz, 3H). ¹³C NMR (126 MHz,CDCl₃) δ 178.57, 169.58, 162.11, 153.72, 150.54, 135.87, 131.02, 130.17,130.08, 121.32, 121.29, 119.64, 118.65, 109.30, 101.48, 82.30, 79.70,49.63, 46.70, 31.88, 30.47, 29.33, 29.28, 28.25, 28.11, 27.11, 22.72,14.18. HRMS (ESI+): Calcd for C₃₃H₄₈N₆O₅ [M+H]⁺: 609.7794, Found:609.3791.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)imino)(2-(3-(1-decyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)carbamate(6w)

6w was prepared using general procedure 5. Purification on a silica gelcolumn with 10-30% ethyl acetate in hexanes produced 6w (19 mg, 43%), aclear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=4.9 Hz, 1H), 7.88-7.74(m, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.15-7.11 (m, 1H), 6.45 (dd, J=3.1, 0.8Hz, 1H), 5.60-5.53 (m, 1H), 4.12-4.03 (m, 2H), 3.90-3.80 (m, 1H),3.80-3.70 (m, 1H), 2.45-2.36 (m, 1H) 2.21-2.10 (m, 2H), 2.00-1.93 (m,1H), 1.78 (h, J=7.7 Hz, 2H), 1.48-1.31 (m, 25H), 1.27-1.12 (m, 17H),0.80 (t, J=6.9 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ 178.58, 169.62,162.15, 153.77, 150.51, 148.72, 135.91, 135.08, 131.05, 130.18, 130.09,126.56, 121.34, 119.26, 119.01, 118.70, 109.64, 109.32, 105.10, 101.52,83.56, 82.35, 79.72, 55.55, 49.65, 46.95, 46.74, 32.00, 30.50, 29.86,29.66, 29.60, 29.41, 28.28, 28.15, 27.16, 27.05, 22.80, 14.24. HRMS(ESI+): Calcd for C₃₅H₅₂N₆O₅ [M+Na]⁺: 659.8143, Found: 659.3884.

Example 2:(S)-amino(2-(3-(1-heptyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7e, Compound 1A)

7e was prepared using general procedure 4 and isolated as a light yellowtinted solid (11 mg, 100%). ¹H NMR (400 MHz, CD₃OD) δ 8.10 (ddd, J=7.9,1.3, 0.8 Hz, 1H), 7.98 (s, 1H), 7.51 (dt, J=8.3, 0.9 Hz, 1H), 7.29 (ddd,J=8.3, 7.1, 1.3 Hz, 1H), 7.22 (ddd, J=8.0, 7.1, 1.0 Hz, 1H), 5.44 (dd,J=7.8, 2.0 Hz, 1H), 4.26 (t, J=7.0 Hz, 2H), 3.82-3.74 (m, 1H), 3.63 (td,J=9.6, 7.2 Hz, 1H), 2.61-2.45 (m, 2H), 2.31-2.21 (m, 1H), 2.14 (ddd,J=12.2, 6.0, 2.8 Hz, 1H), 1.88 (p, J=7.1 Hz, 2H), 1.40-1.18 (m, 9H),0.92-0.81 (m, 3H). ¹³C NMR (400 MHz, CD₃OD) δ 177.32, 166.65, 157.08,138.40, 132.31, 126.65, 123.93, 122.50, 122.21, 111.39, 103.06, 56.44,49.64, 49.43, 49.21, 49.21, 49.17, 49.07, 49.00, 48.99, 48.79, 48.57,48.36, 47.66, 32.84, 32.70, 31.17, 29.97, 27.81, 24.36, 23.56, 14.34.HRMS (ESI+): Calcd for C₂₂H₃₀N₆O [M+H]⁺: 395.5211, Found: 395.2543.

Example 3:(S)-amino(2-(3-(1-octyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7f, Compound 74A)

7f was prepared using general procedure 4 and isolated as a light yellowtinted solid (10 mg, 91%). ¹H NMR (500 MHz, CD₃OD) δ 8.12 (dt, J=8.0,1.0 Hz, 1H), 8.00 (s, 1H), 7.53 (dt, J=8.3, 0.9 Hz, 1H), 7.31 (ddd,J=8.3, 7.1, 1.2 Hz, 1H), 7.26-7.21 (m, 1H), 5.45 (dd, J=7.9, 1.9 Hz,1H), 4.29 (t, J=7.0 Hz, 2H), 3.84-3.77 (m, 1H), 3.67-3.58 (m, 1H),2.63-2.48 (m, 2H), 2.29-2.22 (m, 1H), 2.18-2.07 (m, 1H), 1.92-1.85 (m,2H), 1.38-1.19 (m, 12H), 0.92-0.85 (m, 3H). ¹³C NMR (126 MHz, CD₃OD) δ177.33, 166.66, 157.08, 138.41, 132.32, 126.66, 123.94, 122.51, 122.22,111.41, 103.06, 56.45, 49.51, 49.49, 49.34, 49.32, 49.17, 49.12, 49.02,49.00, 48.83, 48.66, 48.49, 47.66, 32.87, 32.72, 31.16, 30.26, 30.24,27.84, 24.36, 23.64, 14.38. HRMS (ESI+): Calcd for C₂₃H₃₂N₆O [M+H]⁺:409.5477, Found: 409.2728.

Example 4:(S)-amino(2-(3-(1-nonyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7g, Compound 2A)

7g was prepared using general procedure 4 and isolated as a light yellowtinted solid (15 mg, 100%). ¹H NMR (400 MHz, CD₃OD) δ 8.10 (ddd, J=7.9,1.3, 0.7 Hz, 1H), 7.98 (s, 1H), 7.51 (dt, J=8.3, 0.9 Hz, 1H), 7.32-7.26(m, 1H), 7.24-7.19 (m, 1H), 5.45-5.41 (m, 1H), 4.27 (t, J=7.0 Hz, 2H),3.79 (td, J=9.3, 8.9, 2.6 Hz, 1H), 3.63 (td, J=9.6, 7.2 Hz, 1H),2.61-2.47 (m, 1H), 2.29-2.21 (m, 1H) 2.17-2.08 (m, 1H), 1.92-1.82 (m,2H), 1.35-1.21 (m, 14H), 0.88-0.84 (m, 3H). ¹³C NMR (101 MHz, CD₃OD) δ177.32, 166.65, 157.08, 138.41, 132.31, 126.66, 123.93, 122.51, 122.21,111.40, 103.06, 56.44, 47.67, 32.95, 32.71, 31.15, 30.52, 30.27, 27.82,24.36, 23.67, 14.39. HRMS (ESI+): Calcd for C₂₄H₃₄N₆O [M+H]⁺: 423.5743,Found: 423.2890.

Example 5:(S)-amino(2-(3-(1-decyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7h, Compound 7A)

7h was prepared using general procedure 4 and isolated as a light yellowtinted solid (13 mg, 100%). ¹H NMR (500 MHz, CD₃OD) δ 8.14-8.09 (m, 1H),7.98 (s, 1H), 7.55-7.50 (m, 1H), 7.29 (ddd, J=8.3, 7.0, 1.2 Hz, 1H),7.22 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 5.43 (dd, J=7.9, 1.9 Hz, 1H), 4.27(t, J=7.0 Hz, 2H), 3.81-3.76 (m, 1H), 3.65-3.57 (m, 1H), 2.60-2.47 (m,2H), 2.28-2.21 (m, 1H), 1.92-1.84 (m, 2H), 1.40-1.17 (m, 14H), 0.87 (t,J=7.0 Hz, 3H). ¹³C NMR (126 MHz, CD₃OD) δ 205.49, 194.81, 185.23,166.56, 160.48, 154.81, 152.09, 150.67, 150.37, 139.57, 131.22, 84.60,75.83, 61.17, 60.87, 59.31, 58.72, 58.52, 58.42, 55.98, 52.52, 51.85,42.58. HRMS (ESI+): Calcd for C₂₅H₃₆N₆O [M+H]⁺: 437.6009, Found:437.3010.

Example 6:(S)-amino(2-(3-(1-undecyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7i, Compound 4A)

7i was prepared using general procedure 4 and isolated as a light yellowtinted solid (6 mg, 80%). ¹H NMR (500 MHz, CD₃OD) δ 8.10 (d, J=7.8 Hz,1H), 7.98 (s, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.29 (ddd, J=8.3, 7.0, 1.2Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 5.43 (dd, J=7.9, 1.8 Hz, 1H), 4.27 (t,J=7.0 Hz, 2H), 3.79 (td, J=9.2, 2.4 Hz, 1H), 3.66-3.59 (m, 1H), 2.56(dd, J=12.9, 6.4 Hz, 1H), 2.49 (dd, J=13.0, 6.5 Hz, 1H), 2.24 (q, J=6.8,6.2 Hz, 1H), 2.11 (d, J=12.9 Hz, 1H), 1.88 (p, J=7.1 Hz, 2H), 1.39-1.20(m, 18H), 0.88 (t, J=7.0 Hz, 4H). ¹³C NMR (126 MHz, CD₃OD) δ 177.32,166.65, 157.06, 138.41, 132.31, 126.65, 123.94, 122.51, 122.22, 111.41,103.05, 56.46, 47.67, 33.02, 32.73, 31.16, 30.65, 30.60, 30.56, 30.42,30.27, 27.82, 24.37, 23.71, 14.42. HRMS (ESI+): Calcd for C₂₆H₃₈N₆O[M+H]⁺: 451.6275, Found: 451.3192.

Example 7:(S)-amino(2-(3-(1-dodecyl-1H-indol-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7j, Compound 3A)

7j was prepared using general procedure 4 and isolated as a light yellowtinted solid (10 mg, 88%). ¹H NMR (400 MHz, CD₃OD) δ 8.10 (ddd, J=7.9,1.3, 0.8 Hz, 1H), 7.98 (s, 1H), 7.51 (dt, J=8.3, 0.9 Hz, 1H), 7.29 (ddd,J=8.3, 7.1, 1.3 Hz, 1H), 7.22 (ddd, J=8.0, 7.1, 1.0 Hz, 1H), 5.44 (dd,J=7.8, 2.0 Hz, 1H), 4.27 (t, J=7.0 Hz, 2H), 3.85-3.75 (m, 1H), 3.63 (td,J=9.7, 7.3 Hz, 1H), 2.63-2.46 (m, 2H), 2.31-2.20 (m, 1H), 2.21-2.07 (m,1H), 1.88 (t, J=7.1 Hz, 2H), 1.25 (s, 18H), 0.95-0.83 (m, 3H). ¹³C NMR(101 MHz, CD₃OD) δ 177.32, 166.66, 157.08, 138.41, 132.30, 126.66,123.93, 122.51, 122.21, 111.40, 103.07, 56.44, 47.67, 33.04, 32.71,31.15, 30.70, 30.69, 30.58, 30.55, 30.42, 30.26, 27.82, 24.37, 23.71,14.42. HRMS (ESI+): Calcd for C₂₇H₄₀N₆O [M+H]⁺: 465.6540, Found:465.3352.

Example 8:(S)-amino(2-(3-(1-heptyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7k, Compound 8B)

7k was prepared using general procedure 4 and isolated as a light yellowtinted solid (9 mg, 100%). ¹H NMR (500 MHz, CD₃OD) δ 7.86 (dd, J=7.5,0.9 Hz, 1H), 7.64 (dd, J=8.3, 0.9 Hz, 1H), 7.45-7.38 (m, 2H), 7.29 (dd,J=8.3, 7.4 Hz, 1H), 7.09 (dd, J=3.2, 0.8 Hz, 1H), 5.47 (dd, J=7.7, 2.1Hz, 1H), 4.25 (t, J −7.0 Hz, 2H), 3.84-3.78 (m, 1H), 3.67-3.61 (m, 1H),2.64-2.50 (m, 2H), 2.31-2.22 (m, 1H), 2.18-2.09 (m, 1H), 1.86 (p, J=7.1Hz, 2H), 1.32-1.24 (m, 10H), 0.87 (t, J=7.0 Hz, 3H). ¹³C NMR (126 MHz,CD₃OD) δ 177.82, 170.29, 157.14, 138.07, 130.99, 130.90, 127.39, 121.83,121.57, 118.60, 114.25, 56.50, 47.31, 32.88, 32.69, 31.49, 30.00, 28.12,27.89, 24.37, 23.57, 14.34. HRMS (ESI+): Calcd for C₂₂H₃₀N₆O [M+H]⁺:395.5211, Found: 395.2577.

Example 9:(S)-amino(2-(3-(1-octyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7l, Compound 9B)

7l was prepared using general procedure 4 and isolated as a light yellowtinted solid (6 mg, 100%). ¹H NMR (500 MHz, CD₃OD) δ 7.86 (dd, J=7.5,0.9 Hz, 1H), 7.64 (dd, J=8.3, 0.9 Hz, 1H), 7.39 (s, 1H), 7.29 (dd,J=8.2, 7.4 Hz, 1H), 7.09 (dd, J=3.1, 0.8 Hz, 1H), 5.48 (dd, J=7.8, 2.0Hz, 1H), 4.25 (t, J=7.0 Hz, 2H), 3.83-3.78 (m, 1H), 3.66-3.61 (m, 1H),2.62-2.50 (m, 2H), 2.29-2.22 (m, 1H), 2.18-2.07 (m, 1H), 1.89-1.85 (p,J=6.9 Hz, 2H), 1.36-1.22 (m, 16H), 0.87 (t, J=6.9 Hz, 3H). ¹³C NMR (126MHz, CD₃OD) δ 177.81, 170.29, 157.14, 138.06, 130.99, 130.90, 127.40,121.82, 121.57, 118.60, 114.25, 103.03, 61.53, 56.50, 47.30, 32.87,32.69, 31.46, 30.28, 30.26, 27.91, 24.37, 23.64, 20.85, 14.45, 14.37.HRMS (ESI+): Calcd for C₂₃H₃₂N₆O [M+H]⁺: 409.5477, Found: 409.2731.

Example 10:(S)-amino(2-(3-(1-nonyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7m, Compound 10B)

7m was prepared using general procedure 4 and isolated as a light yellowtinted solid (7 mg, 95%). ¹H NMR (500 MHz, CD₃OD) δ 7.90-7.70 (m, 1H),7.45 (s, 1H), 7.42-7.38 (m, 1H), 7.37-7.32 (m, 1H), 7.12-7.08 (m, 1H),5.54-5.48 (m, 1H), 4.34-4.18 (m, 2H), 3.86-3.79 (m, 1H), 3.70-3.64 (m,1H), 2.46-2.46 (m, 2H), 2.29-2.21 (m, 1H), 2.19-2.08 (m, 1H), 1.86 (p,J=6.7 Hz, 1H), 1.42-1.20 (m, 14H), 0.91-0.87 (m, 3H). ¹³C NMR (126 MHz,CD₃OD) δ 176.64, 168.90, 155.73, 135.89, 134.62, 127.33, 122.51, 122.34,121.39, 117.49, 112.85, 55.09, 54.90, 31.55, 31.33, 29.87, 29.13, 28.86,26.40, 22.88, 22.26, 12.97. HRMS (ESI+): Calcd for C₂₄H₃₄N₆O [M+H]⁺:423.5743, Found: 424.2938.

Example 11:(S)-amino(2-(3-(1-decyl-1H-indol-4-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7n, Compound 11B)

7n was prepared using general procedure 4 and isolated as a light yellowtinted solid (6 mg, 81%). ¹H NMR (500 MHz, CD₃OD) δ 7.88 (d, J=7.3 Hz,1H), 7.66 (dd, J=8.3, 5.0 Hz, 1H), 7.40 (d, J=3.1 Hz, 1H), 7.35-7.29 (m,1H), 7.10 (dd, J=6.0, 3.1 Hz, 1H), 5.50 (dd, J=7.8, 2.0 Hz, 1H), 4.27(t, J=6.7 Hz, 2H), 3.85-3.79 (m, 1H), 3.70-3.63 (m, 1H), 2.65-2.52 (m,2H), 2.32-2.23 (m, 1H), 2.18-2.08 (m, 1H), 1.87 (p, J=6.9 Hz, 2H),1.35-1.22 (m, 25H), 0.90-0.87 (m, 3H). ¹³C NMR (126 MHz, CD₃OD) δ177.80, 170.28, 157.13, 138.06, 130.99, 130.90, 128.73, 127.47, 123.75,122.79, 121.82, 121.59, 114.25, 103.04, 56.50, 56.32, 47.31, 33.03,33.01, 32.70, 31.44, 31.29, 30.71, 30.58, 30.54, 30.39, 30.36, 30.26,28.13, 27.87, 24.37, 24.29, 23.72, 23.68, 14.41. HRMS (ESI+): Calcd forC₂₅H₃₆N₆O [M+H]⁺: 437.6009, Found: 437.3033.

Example 12:(S)-amino(2-(3-(1-nonyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7r, Compound 17A)

7r was prepared using general procedure 4 and isolated as a light yellowsolid (7 mg, 95%). ¹H NMR (500 MHz, CD₃OD) δ 8.29 (d, J=1.6 Hz, 1H),7.84 (dd, J=8.7, 1.6 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.32 (d, J=3.2 Hz,1H), 6.56 (dd, J=3.2, 0.8 Hz, 1H), 5.44 (dd, J=7.9, 1.9 Hz, 1H), 4.22(td, J=7.0, 4.4 Hz, 2H), 3.87-3.72 (m, 1H), 3.67-3.58 (m, 1H), 2.63-2.51(m, 1H), 2.25-2.19 (m, 1H), 2.12 (dd, J=8.3, 4.4 Hz, 1H), 1.84 (q, J=7.0Hz, 2H), 1.34-1.07 (m, 15H), 0.86 (d, J=7.1 Hz, 3H). ¹³C NMR (126 MHz,CD₃OD) δ 178.35, 170.83, 157.11, 139.15, 130.86, 130.10, 122.26, 121.98,121.19, 118.15, 111.95, 111.15, 102.92, 56.48, 47.29, 32.97, 32.70,31.39, 30.57, 30.30, 30.29, 27.88, 24.36, 23.69, 14.40. HRMS (ESI+):Calcd for C₂₄H₃₄N₆O [M+H]⁺: 423.5743, Found: 423.2858.

Example 13:(S)-amino(2-(3-(1-octyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7u, Compound 75A)

7u was prepared using general procedure 4 and isolated as a light yellowtinted solid (6 mg, 82%). ¹H NMR (500 MHz, CD₃OD) δ 8.15 (ddd, J=21.7,1.3, 0.7 Hz, 1H), 7.89-7.73 (m, 1H), 7.68 (ddd, J=8.4, 7.1, 0.7 Hz, 1H),7.53-7.39 (m, 1H), 6.54 (dd, J=3.1, 0.9 Hz, 1H), 5.48 (ddd, J=8.0, 3.7,2.1 Hz, 1H), 4.27 (td, J=7.0, 3.4 Hz, 2H), 3.82 (td, J=8.2, 7.2, 5.3 Hz,1H), 3.65-3.56 (m, 1H), 2.65-2.47 (m, 3H), 2.33-2.27 (m, 1H), 2.17-2.08(m, 1H), 1.86 (d, J=14.0 Hz, 2H), 1.36-1.20 (m, 13H), 0.88 (t, J=7.0 Hz,5H). ¹³C NMR (126 MHz, CD₃OD) δ 178.54, 170.93, 157.14, 137.16, 131.99,128.79, 122.27, 119.98, 119.80, 119.64, 119.06, 110.71, 110.13, 102.38,56.52, 47.26, 32.87, 32.79, 31.43, 31.38, 30.29, 30.26, 30.21, 27.91,27.80, 24.40, 23.65, 14.38. HRMS (ESI+): Calcd for C₂₃H₃₂N₆O [M+H]⁺:409.5477, Found: 409.2732.

Example 14:(S)-amino(2-(3-(1-decyl-1H-indol-6-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7w, Compound 18A)

7w was prepared using general procedure 4 and isolated as a light yellowtinted solid (7 mg, 94%). ¹H NMR (500 MHz, CD₃OD) δ 8.20-8.08 (m, 1H),7.85 (dd, J=8.4, 1.3 Hz, 1H), 7.76-7.66 (m, 1H), 7.50 (s, 1H), 6.55-6.54(m, 1H), 5.52-5.45 (m, 1H), 4.26 (t, J=7.0 Hz, 2H), 3.82 (td, J=9.2,8.8, 2.5 Hz, 1H), 3.65 (td, J=9.6, 7.0 Hz, 1H), 2.63-2.51 (m, 2H),2.31-2.21 (m, 1H), 2.18-2.07 (m, 1H), 1.91-1.82 (m, 2H), 1.38-1.11 (m,14H), 0.89 (t, J=7.0 Hz, 3H). HRMS (ESI+): Calcd for C₂₅H₃₆N₆O [M+H]⁺:437.6009, Found: 437.3017.

Examples 15-58 Synthesis and Characterization of Formulae IA and IBCompounds Wherein X is Phenyl

Schemes 3-11 outline general and specific synthetic methodologies forthe preparation of Compound Nos. 5A, 6A, 8A-11A, 19A-50A, 60A, and62A-64A. Compound numbering in Scheme 3 is internal to the Scheme, whilethe subsequent procedures refer where applicable to the final compounds.

General Procedure A. Nucleophilic Aromatic Substitution

4-fluoro-3-(trifluoromethyl)benzonitrile (1 equiv) and the alcohol (1equiv) were added to a microwave vial and cooled in an ice bath, then0.5M potassium tert-butoxide in tetrahydrofuran (1.1 equiv) wascarefully added and allowed to warm to room temperature. The contentswere then heated to 115° C. for 1 minute in the microwave. Aftercooling, celite was added and the solvent was removed under reducedpressure. The resulting powder was subjected to flash chromatography onsilica gel.

General Procedure B. Conversion of Nitrile to Amidoxime

The nitrile (1 equiv) and hydroxylamine hydrochloride (2.2 equiv) weresuspended in absolute ethanol. Triethylamine (2.3 equiv) was added andthe contents were heated to 70° C. for 3 hours. Multi-gram scalereactions were heated overnight. Upon cooling, the solvent wasevaporated under reduced pressure. To the resulting residue, ethylacetate and saturated NaHCO₃ solution were added and stirred until allresidue was dissolved. The mixture was transferred to a separatoryfunnel and the aqueous layer was discarded. The organic layer was washedwith brine, dried over Na₂SO₄, filtered, and concentrated to provide theproduct in sufficiently pure form to be used without furtherpurification.

General Procedure C. PyBOP-Mediated Oxadiazole Formation

The carboxylic acid (1.1 equiv) and PyBOP (1.2 equiv) were dissolved indry N,N-dimethylformamide. N,N-diisopropylethylamine (3 equiv) was addedand stirred for 15 minutes at room temperature. The amidoxime (1 equiv)dissolved in minimal N,N-dimethylformamide was added and the mixture wasstirred for 4 hours at room temperature, then heated to 100° C.overnight. The mixture was allowed to cool to room temperature, thenpoured into a separatory funnel and diluted with ethyl acetate. Theorganics were washed with saturated NaHCO₃, followed by brine. Thebicarbonate wash was back-extracted with ethyl acetate and all organicswere combined, dried over Na₂SO₄ and filtered. Celite was added to theflask and the solvent was evaporated under reduced pressure. Theresulting powder was subjected to flash chromatography on silica gel.

General Procedure D. Guanidine Formation

The Boc-protected pyrrolidine (1 equiv) was dissolved in 4M HCl indioxane and heated to 100° C. in the microwave for 1 minute. The solventwas removed and the crude was reconstituted in dry acetonitrile.tert-butyl(Z)-(((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate(0.9 equiv) and N,N-diisopropylethylamine (3 equiv) were added and themixture was heated to 85° C. for 30 minutes in the microwave (oralternatively, room temperature for 72 hours). Upon cooling, celite wasadded and the solvent was evaporated under reduced pressure. Theresulting powder was subjected to flash chromatography on silica gel.

General Procedure E. Bis-Boc Guanidine Deprotection

The bis-Boc guanidine was dissolved in 4M HCl in dioxane and heated to100° C. in the microwave for 1 minute. The solvent was removed toprovide the final product, which was optionally purified byreverse-phase HPLC.

General Procedure F. Conversion of Carboxylic Acid to Alcohol

The carboxylic acid (1 equiv) and sodium borohydride (5 equiv) weresuspended in dry tetrahydrofuran. The mixture was cooled in an ice bathand a solution of iodine (2 equiv) in THE was added dropwise over 30minutes. The mixture was warmed to room temperature and when thesolution became clear, it was heated to 70° C. for 16 hours. Uponcooling, aqueous 2M sodium hydroxide solution was slowly added andstirred for 1 hour. The mixture was transferred to a seperatory funneland diluted with ethyl acetate. The aqueous layer was discarded and theorganic layer was washed with brine, dried over Na₂SO₄, and filtered.Celite was added and the solvent was evaporated under reduced pressure.The resulting powder was subjected to flash chromatography on silicagel.

General Procedure G. Tert-Butyl Ester Deprotection and Boc-Protection

The tert-butyl ester was dissolved in 4M HCl in dioxane and heated inthe microwave to 100° C. for 1 minute. The solvent was removed underreduced pressure and the crude was reconstituted in dry dichloromethane.Boc-anhydride (1.5 equiv) and triethylamine (3 equiv) were added and themixture was heated in the microwave to 100° C. for 5 minutes. Aqueous 1MHCl solution was added to achieve pH=1 and the product was extractedinto dichloromethane. Celite was added and the solvent was evaporatedunder reduced pressure. The resulting powder was subjected to flashchromatography on silica gel.

General Procedure H. Silyl Ether Deprotection

The TBDPS ether was dissolved in excess 1M tetrabutylammonium fluoridein THF and stirred for 1 hour at room temperature and open to air.Celite was added and the solvent was evaporated under reduced pressure.The resulting powder was subjected to flash chromatography on silicagel.

General Procedure I. Allylation of Benzimidazole

The Benzimidazole was Dissolved in Acetonitrile. Allyl Bromide (1.1Equiv) was added and the mixture was heated in the microwave to 150° C.for 2 minutes. Celite was added and the solvent was removed underreduced pressure. The resulting powder was subjected to flashchromatography on silica gel.

General Procedure J. Alternative Boc deprotection.

The bis-Boc guanidine was dissolved in dichloromethane andtrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 4 hours. The solvent was removed to provide the finalproduct, which was optionally purified by reverse-phase HPLC.

4-(octyloxy)-3-(trifluoromethyl)benzonitrile

Synthesized by General Procedure A. 96% yield, colorless oil; ¹H NMR(600 MHz, Chloroform-d) δ 7.85 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.7, 2.1Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 1.88-1.80 (m,2H), 1.47 (p, J=7.5, 7.1 Hz, 2H), 1.38-1.24 (m, 8H), 0.88 (t, J=6.8 Hz,3H).

N-hydroxy-4-(octyloxy)-3-(trifluoromethyl)benzimidamide

Synthesized by General Procedure B. 100% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 9.25 (s, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.72 (dd,J=8.7, 2.3 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 4.98 (s, 2H), 4.03 (t, J=6.4Hz, 2H), 1.81 (tt, J=12.4, 6.4 Hz, 2H), 1.46 (p, J=7.7, 7.3 Hz, 2H),1.40-1.23 (m, 8H), 0.89 (t, J=6.8 Hz, 3H).

tert-butyl(S)-4,4-difluoro-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedure C. 84% yield, colorless oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.28 (s, 1H), 8.18 (d, J=8.6 Hz, 1H),7.11-7.03 (m, 1H), 5.45-5.20 (m, 1H), 4.11 (t, J=6.4 Hz, 2H), 4.06-3.90(m, 2H), 0.92-0.84 (m, 3H), 2.97-2.85 (m, 1H), 2.80-2.63 (m, 1H),1.91-1.79 (m, 2H), 1.55-1.40 (m, 6H), 1.40-1.22 (m, 13H), 0.89 (t, J=7.0Hz, 3H).

tert-butyl(S)-(((tert-butoxycarbonyl)amino)(4,4-difluoro-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 48% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.29 (d, J=2.1 Hz, 1H), 8.23-8.16 (m, 1H), 7.07 (d,J=8.7 Hz, 1H), 4.79 (dd, J=8.2, 6.9 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H),3.56-3.47 (m, 1H), 3.45-3.35 (m, 1H), 2.89-2.68 (m, 2H), 1.88-1.80 (m,2H), 1.53-1.45 (m, 2H), 1.40-1.23 (m, 9H), 0.89 (t, J=6.9 Hz, 3H).

Example 15:(S)-amino(4,4-difluoro-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 19A)

Synthesized by General Procedure E. 100% yield, white solid; ¹H NMR (600MHz, Methanol-d₄) δ 8.33-8.27 (m, 2H), 7.36 (dd, J=8.7, 2.5 Hz, 1H),5.62 (t, J=8.8 Hz, 1H), 4.19 (td, J=6.2, 2.4 Hz, 2H), 4.03 (dq, J=35.0,13.0 Hz, 2H), 3.28 (dt, J=14.5, 6.0 Hz, 1H), 3.13 (qd, J=14.8, 10.5 Hz,1H), 1.84 (dtd, J=8.0, 6.3, 3.1 Hz, 2H), 1.57-1.46 (m, 2H), 1.46-1.25(m, 8H), 0.90 (td, J=7.0, 2.8 Hz, 3H); ¹³C NMR (151 MHz, cd₃od) δ174.55, 168.91, 161.13, 134.09, 127.29, 118.76, 114.97, 70.39, 68.12,53.83, 52.77, 49.28, 49.14, 49.00, 48.86, 48.72, 38.82, 38.64, 38.46,32.89, 30.31, 30.23, 30.00, 26.89, 23.68, 14.40; MS (ESI+): Calc'd forC₂₂H₂₉F₅N₅O₂ [M+H]: 490.2, Found: 490.8.

tert-butyl(2S,3S)-3-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedure C. 87% yield, colorless oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.29-8.24 (m, 1H), 8.20-8.12 (m, 1H),7.09-7.02 (m, 1H), 5.12-4.93 (m, 1H), 4.61-4.54 (m, 1H), 4.10 (q, J=6.6Hz, 2H), 3.83-3.69 (m, 2H), 2.40-2.28 (m, 1H), 2.09-2.01 (m, 1H), 1.84(p, J=6.7 Hz, 2H), 1.50-1.44 (m, 5H), 1.40-1.24 (m, 14H), 0.89 (t, J=7.0Hz, 2H); MS (ESI+): Calcd for C₂₆H₃₇F₃N₃O₅ [M+H]: 528.3, Found: 528.4.

tert-butyl(((tert-butoxycarbonyl)amino)((2S,3S)-3-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 25% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.25 (d, J=2.1 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz,1H), 7.05 (d, J=8.7 Hz, 1H), 5.53 (dd, J=2.4, 1.0 Hz, 1H), 4.65 (s, 1H),4.14-4.06 (m, 2H), 4.07-3.99 (m, 1H), 3.98-3.91 (m, 1H), 3.13 (s, 1H),2.40-2.32 (m, 1H), 1.88-1.78 (m, 2H), 1.53-1.43 (m, 21H), 1.40-1.23 (m,6H), 0.88 (t, J=7.0 Hz, 3H).

Example 16:amino((2S,3S)-3-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 6A)

Synthesized by General Procedure E. 100% yield, white solid; ¹H NMR (600MHz, Methanol-d4) δ 8.29-8.18 (m, 2H), 7.32 (d, J=8.7 Hz, 1H), 5.26 (t,J=1.0 Hz, 1H), 4.81-4.77 (m, 1H), 4.17 (t, J=6.2 Hz, 2H), 3.89-3.77 (m,2H), 2.28-2.14 (m, 2H), 1.87-1.76 (m, 2H), 1.56-1.47 (m, 2H), 1.44-1.25(m, 8H), 0.90 (d, J=7.0 Hz, 3H); ¹³C NMR (151 MHz, cd₃od) δ 176.97,168.66, 160.88, 157.57, 133.97, 127.06, 119.22, 114.82, 75.98, 70.31,64.78, 47.42, 32.88, 32.47, 30.31, 30.23, 30.00, 26.89, 23.68, 14.41; MS(ESI+): Calc'd for C₂₂H₃₁F₃N₅O₃ [M+H]: 470.2, Found: 470.2.

(2S,3S)-1-(tert-butoxycarbonyl)-3-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-2-carboxylicacid

Synthesized by General Procedure H. 64% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 7.70-7.64 (m, 4H), 7.46-7.37 (m, 6H), 4.33-4.21 (m,1H), 3.73-3.64 (m, 2H), 3.59-3.43 (m, 2H), 2.69-2.54 (m, 1H), 2.08-2.00(m, 1H), 1.89-1.75 (m, 1H), 1.52-1.40 (m, 9H), 1.13-1.05 (m, 9H).

tert-butyl(2S,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedure C. 66% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.31-8.27 (m, 1H), 8.21-8.15 (m, 1H), 7.67-7.62 (m,4H), 7.46-7.35 (m, 6H), 7.10-7.02 (m, 1H), 5.13-5.00 (m, 1H), 4.14-4.08(m, 2H), 3.76-3.63 (m, 2H), 2.20-2.11 (m, 1H), 1.90-1.80 (m, 4H),1.54-1.41 (m, 4H), 1.39-1.25 (m, 17H), 1.05 (s, 9H), 0.89 (t, J=6.8 Hz,3H).

tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 20% yield, yellow solid; ¹H NMR (600MHz, Chloroform-d) δ 8.29 (d, J=2.1 Hz, 1H), 8.19 (dd, J=8.7, 2.2 Hz,1H), 7.70-7.61 (m, 4H), 7.46-7.30 (m, 6H), 7.05 (d, J=8.7 Hz, 1H), 4.53(d, J=5.9 Hz, 1H), 4.16-4.06 (m, 2H), 3.84-3.68 (m, 2H), 3.28-3.20 (m,1H), 3.19-3.12 (m, 1H), 2.79-2.70 (m, 1H), 2.12-2.03 (m, 1H), 1.88-1.80(m, 2H), 1.77-1.68 (m, 1H), 1.53-1.23 (m, 13H), 1.04 (s, 9H), 0.88 (t,J=7.0 Hz, 3H).

tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,3S)-3-(hydroxymethyl)-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure H. 90% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 10.11 (s, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.17 (dd,J=8.7, 2.2 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 5.57-5.55 (m, 0H), 4.10 (t,J=6.4 Hz, 2H), 4.09-4.06 (m, 1H), 3.97-3.89 (m, 1H), 3.85-3.70 (m, 3H),2.75 (s, 1H), 2.30-2.20 (m, 2H), 0.88 (t, J=7.0 Hz, 3H), 5.55-5.52 (m,0H), 1.97-1.70 (m, 5H), 1.54-1.19 (m, 26H).

Example 17:amino((2S,3S)-3-(hydroxymethyl)-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 20A)

Synthesized by General Procedure E. 100% yield, white solid; ¹H NMR (600MHz, Methanol-d₄) δ 8.28-8.17 (m, 2H), 7.33 (d, J=8.7 Hz, 1H), 5.43 (d,J=2.5 Hz, 1H), 4.19 (t, J=6.2 Hz, 2H), 3.81-3.69 (m, 3H), 3.16-3.10 (m,2H), 2.30-2.20 (m, 1H), 2.11-2.03 (m, 1H), 1.88-1.80 (m, 2H), 1.57-1.48(m, 2H), 1.36-1.27 (m, 8H), 0.91 (t, J=6.9 Hz, 3H); MS (ESI+): Calc'dfor C₂₃H₃₃F₃N₅O₃ [M+H]: 484.3, Found: 484.8.

tert-butyl(S)-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

Synthesized by General Procedure C. 85% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.31-8.26 (m, 1H), 8.21-8.15 (m, 1H), 7.09-7.02 (m,1H), 6.13 (dt, J=6.2, 2.1 Hz, 1H), 5.91-5.77 (m, 2H), 4.48-4.28 (m, 2H),4.15-4.07 (m, 2H), 1.88-1.79 (m, 2H), 1.53-1.44 (m, 5H), 1.40-1.23 (m,14H), 0.88 (t, J=7.0 Hz, 3H).

tert-butyl(S)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl)methylene)carbamate

Synthesized by General Procedure D. 34% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 10.11 (s, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.17 (dd,J=8.7, 2.2 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 6.46-6.40 (m, 1H), 6.19-6.11(m, 1H), 5.91-5.86 (m, 1H), 4.81-4.74 (m, 1H), 4.47 (d, J=16.4 Hz, 1H),8.29-8.24 (m, 0H), 1.88-1.80 (m, 2H), 8.24-8.10 (m, 0H), 4.15-4.08 (m,2H), 1.57-1.23 (m, 28H), 0.88 (t, J=6.9 Hz, 3H).

Example 18:(S)-amino(2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-2,5-dihydro-1H-pyrrol-1-yl)methaniminiumchloride (Compound 21A)

Synthesized by General Procedure E. 95% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 8.26-8.18 (m, 1H), 8.17-8.07 (m, 1H), 7.12-7.04 (m,1H), 6.40-6.23 (m, 1H), 6.14-6.00 (m, 1H), 4.15-4.06 (m, 1H), 1.90-1.78(m, 2H), 1.74-1.56 (m, 4H), 1.54-1.44 (m, 2H), 1.42-1.20 (m, 8H),0.98-0.81 (m, 3H); MS (ESI+): Calc'd for C₂₂H₂₉F₃N₅O₂ [M+H]: 452.2,Found: 452.6.

tert-butyl(2S,4R)-4-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedure C. 73% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.28 (d, J=2.2 Hz, 1H), 8.18 (dd, J=8.8, 2.1 Hz,1H), 7.07 (d, J=8.9 Hz, 1H), 5.23 (t, J=8.0 Hz, 1H), 4.69-4.63 (m, 1H),4.13-4.08 (m, 3H), 3.82 (dd, J=11.8, 4.3 Hz, 1H), 3.70 (d, J=11.9 Hz,1H), 2.50-2.47 (m, 1H), 2.36-2.30 (m, 1H), 1.88-1.80 (m, 2H), 1.53-1.45(m, 2H), 1.40-1.23 (m, 17H), 0.89 (t, J=7.0 Hz, 3H).

tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,4R)-4-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 21% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.27 (d, J=2.1 Hz, 1H), 8.24-8.13 (m, 1H),7.07-7.02 (m, 1H), 5.86 (t, J=8.2 Hz, 1H), 4.66 (d, J=4.2 Hz, 1H), 4.10(t, J=6.4 Hz, 2H), 4.05 (dd, J=12.5, 3.4 Hz, 1H), 3.80-3.74 (m, 1H),2.79 (s, 1H), 2.62-2.56 (m, 1H), 2.41-2.33 (m, 1H), 1.88-1.80 (m, 2H),1.55-1.40 (m, 18H), 1.39-1.23 (m, 10H), 0.88 (t, J=7.0 Hz, 3H).

Example 19:amino((2S,4R)-4-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 8A)

Synthesized by General Procedure E. 100% yield, white solid; ¹H NMR (600MHz, Methanol-d₄) δ 8.27-8.20 (m, 2H), 7.33 (d, J=8.7 Hz, 1H), 5.60-5.54(m, 1H), 4.65-4.59 (m, 1H), 4.19 (t, J=6.2 Hz, 2H), 3.91-3.85 (m, 1H),3.63-3.56 (m, 1H), 2.68-2.61 (m, 1H), 2.56-2.48 (m, 1H), 1.88-1.80 (m,2H), 1.57-1.48 (m, 2H), 1.44-1.27 (m, 8H), 0.91 (t, J=7.0 Hz, 3H); MS(ESI+): Calc'd for C₂₂H₃₁F₃N₅O₃ [M+H]: 470.2, Found: 470.8.

tert-butyl(2S,4S)-4-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedure C. 46% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.26-8.21 (m, 1H), 8.13 (dd, J=8.7, 2.1 Hz, 1H),7.06 (t, J=10.0 Hz, 1H), 5.13 (d, J=9.3 Hz, 1H), 4.53 (t, J=4.7 Hz, 1H),4.15-4.08 (m, 3H), 3.84 (d, J=12.0 Hz, 1H), 3.77-3.65 (m, 1H), 2.63-2.53(m, 1H), 2.32 (t, J=14.4 Hz, 1H), 1.88-1.80 (m, 2H), 1.52-1.41 (m, 5H),1.40-1.25 (m, 14H), 0.89 (t, J=7.0 Hz, 3H).

tert-butyl((E)-((tert-butoxycarbonyl)amino)-((2S,4S)-4-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 26% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 10.06 (s, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.12 (dd,J=8.7, 2.2 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 5.61 (d, J=8.8 Hz, 1H), 4.58(s, 1H), 4.13-4.04 (m, 3H), 3.90 (d, J=12.5 Hz, 1H), 2.64-2.56 (m, 1H),2.36 (d, J=14.1 Hz, 1H), 1.84 (ddt, J=9.3, 7.9, 6.3 Hz, 2H), 1.57-1.22(m, 28H), 0.88 (t, J=7.0 Hz, 3H).

Example 20:amino((2S,4S)-4-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 9A)

Synthesized by General Procedure E. 88% yield, white solid; ¹H NMR (600MHz, Methanol-d4) δ 8.26-8.20 (m, 2H), 7.32 (d, J=8.7 Hz, 1H), 5.40 (dd,J=7.9, 1.8 Hz, 1H), 4.65-4.59 (m, 1H), 4.18 (t, J=6.2 Hz, 2H), 3.77 (td,J=10.7, 4.6 Hz, 1H), 3.70-3.59 (m, 1H), 2.73-2.62 (m, 2H), 1.88-1.80 (m,2H), 1.57-1.48 (m, 2H), 1.44-1.27 (m, 8H), 0.91 (t, J=7.0 Hz, 3H); MS(ESI+): Calc'd for C₂₂H₃₁F₃N₅O₃ [M+H]: 470.2, Found: 470.8.

tert-butyl(2S,3R)-3-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedure C. 15% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.29 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.10-7.05 (m,2H), 5.15 (d, J=6.5 Hz, 1H), 4.76-4.71 (m, 1H), 4.11 (t, J=6.2 Hz, 2H),3.83-3.75 (m, 1H), 3.64-3.56 (m, 1H), 2.30-2.17 (m, 2H), 1.88-1.80 (m,2H), 1.53-1.44 (m, 5H), 1.40-1.24 (m, 14H), 0.89 (t, J=7.0 Hz, 3H).

tert-butyl(((tert-butoxycarbonyl)amino)((2S,3R)-3-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 29% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.29-8.25 (m, 1H), 8.21-8.15 (m, 1H), 7.08-7.03 (m,1H), 5.88 (s, 1H), 4.84-4.81 (m, 1H), 4.22-4.19 (m, 1H), 4.10 (td,J=6.4, 2.0 Hz, 2H), 3.81-3.78 (m, 1H), 2.83 (s, 1H), 2.29-2.24 (m, 2H),1.88-1.80 (m, 2H), 1.53-1.39 (m, 18H), 1.38-1.24 (m, 10H), 0.88 (t,J=7.0 Hz, 3H).

Example 21:amino((2S,3R)-3-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 10A)

Synthesized by General Procedure E. 88% yield, white solid; ¹H NMR (600MHz, Methanol-d₄) δ 8.28-8.21 (m, 2H), 7.33 (d, J=8.7 Hz, 1H), 5.45 (d,J=6.8 Hz, 1H), 4.18 (t, J=6.2 Hz, 2H), 3.96-3.88 (m, 1H), 3.72-3.63 (m,1H), 2.41-2.33 (m, 1H), 2.23-2.14 (m, 1H), 1.88-1.80 (m, 2H), 1.57-1.49(m, 2H), 1.42-1.27 (m, 8H), 0.91 (t, J=7.0 Hz, 3H); MS (ESI+): Calc'dfor C₂₂H₃₁F₃N₅O₃ [M+H]: 470.2, Found: 470.8.

3-(4-(trifluoromethyl)phenyl)propan-1-ol

Synthesized by General Procedure F. 100% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 7.54 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H),3.68 (t, J=6.3 Hz, 2H), 2.78 (t, J=7.7 Hz, 2H), 1.92-1.88 (m, 2H), 1.61(s, 1H).

3-(trifluoromethyl)-4-(3-(4-(trifluoromethyl)phenyl)propoxy)benzonitrile

Synthesized by General Procedure A. 81% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 7.87 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.7, 2.1 Hz,1H), 7.54 (d, J=8.0 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 7.02 (d, J=8.7 Hz,1H), 4.10 (t, J=5.9 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H), 2.23-2.14 (m, 2H).

tert-butyl(2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(3-(4-(trifluoromethyl)phenyl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 74% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.33-8.30 (m, 1H), 8.21-8.16 (m, 1H), 7.54 (d,J=7.7 Hz, 2H), 7.32 (d, J=7.7 Hz, 2H), 7.02 (t, J=10.1 Hz, 1H), 4.96 (s,1H), 4.58 (d, J=17.5 Hz, 1H), 4.09 (t, J=5.7 Hz, 2H), 3.84-3.72 (m, 2H),2.93 (t, J=7.5 Hz, 2H), 2.21-2.15 (m, 2H), 2.07-2.04 (m, 2H), 1.48 (s,3H), 1.32 (s, 6H).

tert-butyl(((tert-butoxycarbonyl)amino)((2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(3-(4-(trifluoromethyl)phenyl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 22% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.29 (d, J=2.1 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz,1H), 7.54 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.8 Hz,1H), 5.61-5.57 (m, 1H), 4.69 (s, 1H), 4.12-4.04 (m, 3H), 3.18 (s, 1H),2.93 (t, J=7.5 Hz, 2H), 2.39-2.32 (m, 1H), 2.22-2.12 (m, 3H), 1.47 (s,18H).

Example 22:amino((2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(3-(4-(trifluoromethyl)phenyl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 22A)

Synthesized by General Procedure E. 100% yield, white solid; ¹H NMR (600MHz, Methanol-d₄) δ 8.28-8.22 (m, 2H), 7.58 (d, J=7.9 Hz, 2H), 7.41 (d,J=8.0 Hz, 2H), 7.36-7.28 (m, 1H), 5.24 (t, J=1.0 Hz, 1H), 4.79 (dt,J=3.7, 1.3 Hz, 1H), 4.29-4.15 (m, 2H), 3.97-3.90 (m, 0H), 3.89-3.78 (m,2H), 3.66 (s, 1H), 2.94 (t, J=7.6 Hz, 2H), 2.28-2.14 (m, 4H); ¹³C NMR(151 MHz, cd₃od) δ 175.58, 167.22, 159.22, 156.16, 145.87, 132.63,128.76, 124.97, 124.94, 124.92, 118.08, 113.42, 74.57, 67.50, 66.70,63.38, 47.99, 47.85, 47.71, 47.57, 47.42, 47.28, 47.14, 45.99, 31.18,31.05, 30.07; MS (ESI+): Calc'd for C₂₄H₂₄F₆N₅O₃ [M+H]: 544.2, Found:544.6.

2-(4-(trifluoromethyl)phenyl)ethan-1-ol

Synthesized by General Procedure F. 69% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 7.34 (d, J=7.9 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H),4.19 (s, 1H), 3.61 (t, J=6.8 Hz, 1H), 2.70 (t, J=6.9 Hz, 1H).

3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)benzonitrile

Synthesized by General Procedure A. 30% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 7.86 (d, J=2.0 Hz, 1H), 7.77 (dd, J=8.7, 2.1 Hz,1H), 7.58 (d, J=8.0 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 7.03 (d, J=8.7 Hz,1H), 4.32 (t, J=6.3 Hz, 2H), 3.22 (t, J=6.3 Hz, 2H).

tert-butyl(2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 62% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.30-8.24 (m, 1H), 8.20-8.13 (m, 1H), 7.58 (d,J=8.0 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 7.06-6.99 (m, 1H), 4.94 (s, 1H),4.56 (d, J=19.9 Hz, 1H), 4.32 (q, J=6.0 Hz, 2H), 3.82-3.68 (m, 2H), 3.22(t, J=6.3 Hz, 2H), 2.39-2.28 (m, 1H), 2.08-2.01 (m, 2H), 1.47 (s, 3H),1.31-1.24 (m, 6H).

tert-butyl(((tert-butoxycarbonyl)amino)((2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 20% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.27 (d, J=2.1 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz,1H), 7.58 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.7 Hz,1H), 5.58 (s, 1H), 4.66 (s, 1H), 4.32 (t, J=6.3 Hz, 2H), 4.09-4.01 (m,1H), 3.98-3.92 (m, 1H), 3.22 (t, J=6.3 Hz, 2H), 2.85 (s, 1H), 2.40-2.32(m, 1H), 2.16-2.10 (m, 1H), 1.46 (s, 18H).

Example 23:amino((2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 23A)

Synthesized by General Procedure E. 100% yield, white solid; ¹H NMR (600MHz, Methanol-d4) δ 8.26-8.19 (m, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.53 (d,J=8.0 Hz, 2H), 7.35 (d, J=8.8 Hz, 1H), 5.21 (s, 1H), 4.78 (d, J=3.6 Hz,1H), 4.44 (t, J=6.3 Hz, 2H), 4.23-4.18 (m, 1H), 3.87-3.78 (m, 1H),3.77-3.62 (m, 2H), 3.24 (t, J=6.2 Hz, 2H), 2.24-2.15 (m, 1H); MS (ESI+):Calc'd for C₂₃H₂₂F₆N₅O₃ [M+H]: 530.2, Found: 530.8.

3-(trifluoromethyl)-4-((4-(trifluoromethyl)benzyl)oxy)benzonitrile

Synthesized by General Procedure A. 89% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 7.91 (d, J=2.1 Hz, 1H), 7.79 (dd, J=8.8, 2.1 Hz,1H), 7.68 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.7 Hz,1H), 5.32 (s, 2H).

tert-butyl(2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 91% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.33 (d, J=9.3 Hz, 1H), 8.19 (t, J=8.8 Hz,1H), 7.67 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.14-7.07 (m, 1H),5.31 (d, J=8.1 Hz, 2H), 5.10 (s, 0H), 4.96 (s, 1H), 4.57 (d, J=16.8 Hz,1H), 3.83-3.69 (m, 2H), 2.40-2.28 (m, 1H), 2.08-2.01 (m, 2H), 1.47 (s,3H), 1.31 (s, 6H).

tert-butyl(((tert-butoxycarbonyl)amino)((2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 46% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.31 (d, J=2.1 Hz, 1H), 8.19 (dd, J=8.7, 2.1 Hz,1H), 7.67 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.8 Hz,1H), 5.69 (d, J=1.7 Hz, 1H), 5.31 (s, 2H), 4.77-4.72 (m, 1H), 4.18-4.08(m, 1H), 3.97-3.91 (m, 1H), 2.37-2.28 (m, 1H), 2.21-2.15 (m, 1H), 1.47(s, 18H).

Example 24:amino((2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 24A)

Synthesized by General Procedure E. 94% yield, white solid; ¹H NMR (600MHz, Methanol-d₄) δ 8.26 (d, J=2.2 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H),7.73-7.65 (m, 4H), 7.46-7.41 (m, 1H), 6.59 (t, J=2.2 Hz, 1H), 5.42 (s,2H), 5.27 (t, J=1.0 Hz, 1H), 4.81-4.77 (m, 1H), 3.89-3.79 (m, 2H),2.28-2.14 (m, 2H); ¹³C NMR (151 MHz, cd₃od) δ 175.66, 167.13, 158.49,156.17, 140.48, 133.63, 132.66, 127.11, 125.80, 125.13, 125.11, 125.09,125.06, 118.70, 114.07, 74.58, 69.46, 66.70, 63.38, 46.03, 31.05; MS(ESI+): Calc'd for C₂₂H₃₁F₃N₅O₄ [M+H]: 516.2, Found: 516.4.

4-(4-(trifluoromethyl)phenyl)butan-1-ol

Synthesized by General Procedure F. 24% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 7.53 (d, J=8.0 Hz, 1H), 7.29 (d, J=7.9 Hz, 2H),3.67 (t, J=6.4 Hz, 2H), 2.71 (t, J=7.7 Hz, 2H), 1.76-1.68 (m, 1H),1.65-1.57 (m, 2H), 1.44 (s, 1H).

3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)benzonitrile

Synthesized by General Procedure A. 85% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 7.86 (d, J=2.2 Hz, 1H), 7.77 (dd, J=8.7, 2.1 Hz,1H), 7.54 (d, J=7.9 Hz, 2H), 7.30 (d, J=7.9 Hz, 2H), 7.03 (d, J=8.7 Hz,1H), 4.12 (t, J=5.5 Hz, 2H), 2.76 (t, J=7.0 Hz, 2H), 1.93-1.82 (m, 4H).

tert-butyl(2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 74% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.30-8.25 (m, 1H), 8.20-8.14 (m, 1H), 7.54 (d,J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.07-7.00 (m, 1H), 4.95 (d, J=1.9Hz, 1H), 4.57 (d, J=17.8 Hz, 1H), 4.15-4.10 (m, 2H), 3.83-3.67 (m, 2H),2.79-2.73 (m, 2H), 2.40-2.28 (m, 1H), 2.09-2.01 (m, 1H), 1.92-1.84 (m,4H), 1.47 (s, 3H), 1.31 (s, 6H).

tert-butyl(((tert-butoxycarbonyl)amino)((2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 21% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.27 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz,1H), 7.54 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.04 (d, J=8.8 Hz,1H), 5.57-5.53 (m, 1H), 4.65 (s, 1H), 4.15-4.10 (m, 2H), 4.07-3.92 (m,2H), 2.79-2.73 (m, 3H), 2.42-2.33 (m, 1H), 2.16-2.09 (m, 1H), 1.88 (h,J=2.5 Hz, 4H), 1.46 (s, 18H).

Example 25:amino((2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 25A)

Synthesized by General Procedure E. 87% yield, white solid; ¹H NMR (600MHz, Methanol-d₄) δ 8.27-8.19 (m, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.40 (d,J=8.0 Hz, 2H), 7.31 (d, J=8.7 Hz, 1H), 5.25 (t, J=1.0 Hz, 1H), 4.79 (dt,J=3.8, 1.2 Hz, 1H), 4.21 (h, J=2.9 Hz, 2H), 3.89-3.79 (m, 2H), 2.82-2.76(m, 2H), 2.27-2.14 (m, 2H), 1.94-1.84 (m, 4H); ¹³C NMR (151 MHz, cd₃od)δ 175.56, 167.23, 156.16, 146.75, 132.56, 128.61, 125.66, 124.80,124.77, 124.75, 124.72, 117.92, 113.45, 74.57, 68.53, 63.37, 45.99,34.64, 31.05, 28.04, 26.98; MS (ESI+): Calc'd for C₂₅H₂₆F₆N₅O₃ [M+H]:558.2, Found: 558.4.

tert-butyl(S)-2-(3-(3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 69% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.30 (d, J=2.6 Hz, 1H), 8.19 (dd, J=8.3, 2.4Hz, 1H), 7.54 (d, J=8.0 Hz, 3H), 7.31 (d, J=8.0 Hz, 2H), 7.07-7.00 (m,1H), 5.21-5.03 (m, 1H), 4.15-4.10 (m, 2H), 3.75-3.66 (m, 1H), 3.61-3.45(m, 1H), 2.79-2.73 (m, 2H), 2.46-2.33 (m, 1H), 2.20-2.09 (m, 2H),2.06-1.96 (m, 1H), 1.92-1.84 (m, 4H), 1.46 (s, 3H), 1.30 (s, 6H).

tert-butyl(S)-(((tert-butoxycarbonyl)amino)(2-(3-(3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 36% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.28 (d, J=2.1 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz,1H), 7.53 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.7 Hz,1H), 5.59 (dd, J=7.9, 4.6 Hz, 1H), 4.14-4.09 (m, 2H), 3.93-3.85 (m, 1H),3.79 (s, 1H), 2.78-2.73 (m, 3H), 2.44 (dd, J=13.6, 7.2 Hz, 1H),2.21-2.14 (m, 2H), 2.07-1.99 (m, 1H), 1.90-1.86 (m, 4H), 1.44 (d, J=39.8Hz, 18H).

Example 26:(S)-amino(2-(3-(3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 26A)

Synthesized by General Procedure E. 76% yield, white solid; ¹H NMR (600MHz, Methanol-d₄) δ 8.26-8.20 (m, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.41 (d,J=8.0 Hz, 2H), 7.31 (d, J=8.7 Hz, 1H), 5.49-5.44 (m, 1H), 4.25-4.18 (m,2H), 3.82-3.56 (m, 4H), 2.79 (t, J=6.6 Hz, 2H), 2.63-2.53 (m, 1H),2.51-2.44 (m, 1H), 2.32-2.20 (m, 1H), 2.15-2.03 (m, 1H), 1.89 (dp,J=4.7, 2.8 Hz, 4H); ¹³C NMR (151 MHz, cd₃od) δ 177.78, 167.11, 159.30,155.66, 146.76, 132.52, 128.61, 125.65, 124.78, 124.75, 124.73, 118.03,113.43, 68.52, 66.70, 55.03, 34.64, 31.29, 28.05, 26.99, 22.89; MS(ESI+): Calc'd for C₂₅H₂₆F₆N₅O₂ [M+H]: 542.2, Found: 542.4.

3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propan-1-ol

Synthesized by General Procedure F. 95% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 6.78 (d, J=8.2 Hz, 1H), 6.72-6.64 (m, 2H),4.29-4.20 (m, 4H), 3.66 (t, J=6.4 Hz, 2H), 2.63-2.57 (m, 2H) 1.89-1.80(m, 2H).

4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-3-(trifluoromethyl)benzonitrile

Synthesized by General Procedure A. 100% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 7.87 (d, J=2.1 Hz, 1H), 7.76 (dd, J=8.7, 2.2 Hz,1H), 7.00 (d, J=8.7 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.69 (d, J=2.1 Hz,1H), 6.64 (dd, J=8.2, 2.1 Hz, 1H), 4.30-4.20 (m, 4H), 4.07 (t, J=6.1 Hz,2H), 2.73 (t, J=7.4 Hz, 2H), 2.18-2.08 (m, 2H).

tert-butyl(2S,3S)-2-(3-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 57% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.31-8.28 (m, 1H), 8.19-8.14 (m, 1H),7.05-6.98 (m, 1H), 6.78 (d, J=8.2 Hz, 1H), 6.71 (d, J=2.1 Hz, 1H), 6.66(dd, J=8.2, 2.1 Hz, 1H), 4.95 (s, 1H), 4.58 (d, J=17.4 Hz, 1H),4.27-4.19 (m, 4H), 4.08 (t, J=6.0 Hz, 3H), 3.83-3.72 (m, 1H), 2.74 (t,J=7.4 Hz, 2H), 2.36-2.33 (m, 1H), 2.16-2.08 (m, 2H), 2.07-2.03 (m, 1H),1.48 (s, 3H), 1.32 (s, 6H).

tert-butyl(((tert-butoxycarbonyl)amino)((2S,3S)-2-(3-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 18% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.27 (d, J=2.1 Hz, 1H), 8.16 (dd, J=8.7, 2.1 Hz,1H), 7.01 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.71 (d, J=2.1 Hz,1H), 6.66 (dd, J=8.2, 2.1 Hz, 1H), 5.56 (dd, J=2.3, 1.0 Hz, 1H), 4.67(s, 1H), 4.27-4.20 (m, 4H), 4.10-4.02 (m, 4H), 3.98-3.92 (m, 1H), 3.03(s, 1H), 2.74 (t, J=7.4 Hz, 2H), 2.41-2.32 (m, 1H), 2.19-2.07 (m, 3H),1.46 (s, 18H).

Example 27:(S)-amino(2-(3-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 27)

Synthesized by General Procedure E. 98% yield, white solid; 1H NMR (600MHz, Methanol-d4) δ 8.35-8.04 (m, 2H), 7.36-7.10 (m, 1H), 6.75-6.57 (m,3H), 4.86 (s, 4H), 4.21-4.15 (m, 3H), 4.15-3.96 (m, 2H), 3.66 (s, 3H),2.78-2.59 (m, 2H), 2.14-1.93 (m, 2H); MS (ESI+): Calc'd for C₂₅H₂₇F₃N₅O₅[M+H]: 534.2, Found: 534.4.

3-(3,4-dichlorophenyl)propan-1-ol

Synthesized by General Procedure F. 100% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 7.34 (d, J=8.2 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H),7.03 (dd, J=8.2, 2.1 Hz, 1H), 3.69 (t, J=6.4 Hz, 2H), 2.67 (t, J=7.7 Hz,2H), 1.91-1.84 (m, 2H).

4-(3-(3,4-dichlorophenyl)propoxy)-3-(trifluoromethyl)benzonitrile

Synthesized by General Procedure A. 47% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 7.88 (d, J=2.1 Hz, 1H), 7.78 (dd, J=8.7, 2.1 Hz,1H), 7.35 (d, J=8.2 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.04-6.99 (m, 2H),4.08 (t, J=5.9 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.19-2.11 (m, 2H).

tert-butyl(2S,3S)-2-(3-(4-(3-(3,4-dichlorophenyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidine-1-carboxylate

Synthesized by General Procedure B and C. 65% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.30 (d, J=7.8 Hz, 1H), 8.21-8.16 (m, 1H),7.34 (d, J=8.2 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.08-6.98 (m, 2H), 4.96(s, 1H), 4.58 (d, J=17.9 Hz, 1H), 4.11-4.06 (m, 2H), 3.83-3.71 (m, 2H),2.82 (t, J=7.5 Hz, 2H), 2.39-2.31 (m, 2H), 2.19-2.10 (m, 2H), 2.09-2.03(m, 1H), 1.48 (s, 3H), 1.31 (s, 6H).

tert-butyl(((tert-butoxycarbonyl)amino)((2S,3S)-2-(3-(4-(3-(3,4-dichlorophenyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 10% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.29 (d, J=2.1 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz,1H), 7.34 (d, J=8.2 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.06-6.99 (m, 2H),5.54 (d, J=2.3 Hz, 1H), 4.65 (s, 1H), 4.10-3.99 (m, 3H), 3.99-3.92 (m,1H), 2.88 (s, 1H), 2.82 (t, J=7.5 Hz, 2H), 2.42-2.33 (m, 1H), 2.19-2.09(m, 3H), 1.46 (s, 18H).

Example 28:(S)-amino(2-(3-(4-(3-(3,4-dichlorophenyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 28)

Synthesized by General Procedure E. 100% yield, white solid; ¹H NMR (600MHz, Methanol-d4) δ 8.28-8.21 (m, 2H), 7.41 (d, J=8.2 Hz, 1H), 7.37 (d,J=2.2 Hz, 1H), 7.33-7.28 (m, 1H), 7.15 (dd, J=8.3, 2.0 Hz, 1H), 5.25 (d,J=1.0 Hz, 1H), 4.79 (dd, J=3.6, 1.3 Hz, 1H), 4.16 (t, J=5.9 Hz, 2H),3.89-3.78 (m, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.28-2.10 (m, 4H); MS (ESI+):Calc'd for C₂₃H₂₃Cl₂F₃N₅O₃ [M+H]: 544.1, Found: 544.4.

tert-butyl(S)-2-(3-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 62% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.30 (s, 1H), 8.17 (d, J=8.2 Hz, 1H),7.05-6.98 (m, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.71 (d, J=2.1 Hz, 1H), 6.66(dd, J=8.2, 2.1 Hz, 1H), 5.06 (dd, J=8.3, 3.7 Hz, 1H), 4.23 (d, J=1.1Hz, 4H), 4.08 (t, J=5.9 Hz, 2H), 3.76-3.66 (m, 1H), 3.60-3.53 (m, 1H),2.74 (t, J=7.4 Hz, 2H), 2.46-2.32 (m, 1H), 2.20-2.08 (m, 4H), 2.06-1.97(m, 1H), 1.46 (s, 3H), 1.30 (s, 6H).

tert-butyl(S)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 29% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 10.12 (s, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.17 (dd,J=8.7, 2.1 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.71(d, J=2.1 Hz, 1H), 6.66 (dd, J=8.2, 2.1 Hz, 1H), 5.61 (dd, J=7.9, 4.5Hz, 1H), 4.23 (s, 4H), 4.15-4.05 (m, 2H), 3.94-3.87 (m, 1H), 3.80 (s,1H), 2.74 (t, J=7.4 Hz, 2H), 2.50-2.42 (m, 1H), 2.24-1.99 (m, 5H), 1.58(s, 0H), 1.46 (s, 18H).

Example 29:(S)-amino(2-(3-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 29)

Synthesized by General Procedure E. 95% yield, white solid; ¹H NMR (600MHz, Methanol-d4) δ 8.23 (d, J=7.8 Hz, 1H), 7.29-7.24 (m, 1H), 6.71 (d,J=8.2 Hz, 1H), 6.68-6.59 (m, 2H), 5.46 (dd, J=8.1, 1.7 Hz, 1H),4.22-4.15 (m, 4H), 4.12 (t, J=5.9 Hz, 2H), 3.82-3.71 (m, 1H), 3.68-3.56(m, 2H), 2.71 (t, J=7.4 Hz, 2H), 2.62-2.53 (m, 1H), 2.52-2.44 (m, 1H),2.28-2.20 (m, 1H), 2.10-2.04 (m, 3H); MS (ESI+): Calc'd for C₂₅H₂₇F₃N₅O₄[M+H]: 518.2, Found: 518.6.

tert-butyl(2S,4R)-2-(3-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-4-hydroxypyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 44% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.30 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.7, 2.1Hz, 1H), 7.02 (d, J=9.1 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.71 (d, J=2.1Hz, 1H), 6.66 (dd, J=8.2, 2.1 Hz, 1H), 5.35-5.20 (m, 2H), 4.69-4.63 (m,1H), 4.27-4.20 (m, 4H), 4.08 (t, J=6.0 Hz, 2H), 3.81 (dd, J=11.8, 4.3Hz, 1H), 3.70 (d, J=11.9 Hz, 1H), 3.59 (d, J=11.5 Hz, 0H), 2.74 (t,J=7.4 Hz, 2H), 2.52-2.45 (m, 1H), 2.36-2.28 (m, 1H), 2.15-2.08 (m, 2H),1.45 (s, 3H), 1.28 (s, 6H).

tert-butyl(((tert-butoxycarbonyl)amino)((2S,4R)-2-(3-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-4-hydroxypyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 29% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.29 (d, J=2.1 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz,1H), 7.65 (d, J=2.2 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.77 (d, J=8.2 Hz,1H), 6.71 (d, J=2.1 Hz, 1H), 6.66 (dd, J=8.2, 2.1 Hz, 1H), 5.91 (t,J=8.3 Hz, 1H), 4.65 (d, J=4.0 Hz, 1H), 4.23 (s, 4H), 4.11-4.02 (m, 0H),3.80 (d, J=12.7 Hz, 1H), 2.74 (t, J=7.4 Hz, 2H), 2.64-2.56 (m, 1H),2.42-2.36 (m, 1H), 2.15-2.08 (m, 2H), 1.46 (s, 18H).

Example 30:amino((2S,4R)-2-(3-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-4-hydroxypyrrolidin-1-yl)methaniminiumchloride (Compound 60A)

Synthesized by General Procedure E. 98% yield, white solid; ¹H NMR (600MHz, Methanol-d4) δ 8.31 (d, J=2.6 Hz, 1H), 8.23 (d, J=7.5 Hz, 2H),7.30-7.24 (m, 1H), 6.84 (t, J=2.6 Hz, 0H), 6.71 (d, J=8.2 Hz, 1H),6.68-6.61 (m, 2H), 5.61-5.55 (m, 1H), 4.65-4.59 (m, 1H), 4.19 (s, 4H),4.13 (t, J=6.0 Hz, 2H), 3.89 (dd, J=10.7, 4.6 Hz, 1H), 3.63-3.56 (m,1H), 2.75-2.61 (m, 3H), 2.56-2.48 (m, 1H), 2.12-2.04 (m, 2H); MS (ESI+):Calc'd for C₂₅H₂₇F₃N₅O₅ [M+H]: 534.2, Found: 534.4.

tert-butyl(S)-2-(3-(4-(3-(3,4-dichlorophenyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 74% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.31 (d, J=2.4 Hz, 1H), 8.21-8.16 (m, 1H),7.34 (d, J=8.1 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.06-6.98 (m, 2H), 5.06(dd, J=8.0, 3.7 Hz, 1H), 4.08 (t, J=6.0 Hz, 2H), 3.76-3.69 (m, 1H),3.61-3.46 (m, 1H), 2.83 (t, J=7.5 Hz, 2H), 2.46-2.34 (m, 1H), 2.20-2.10(m, 4H), 2.06-1.98 (m, 1H), 1.47 (s, 3H), 1.30 (s, 6H).

tert-butyl(S)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(3-(3,4-dichlorophenyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 34% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 10.12 (s, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.18 (dd,J=8.7, 2.2 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H),7.06-6.99 (m, 2H), 5.61 (dd, J=7.9, 4.6 Hz, 1H), 4.08 (t, J=5.8 Hz, 2H),3.91 (dt, J=11.5, 7.0 Hz, 1H), 3.80 (s, 1H), 2.82 (t, J=7.5 Hz, 2H),2.45 (dq, J=15.8, 8.8, 8.2 Hz, 1H), 2.25-2.10 (m, 4H), 2.09-1.99 (m,1H), 1.46 (s, 18H).

Example 31:(S)-amino(2-(3-(4-(3-(3,4-dichlorophenyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 30A)

Synthesized by General Procedure E. 80% yield, white solid; ¹H NMR (600MHz, Methanol-d4) δ 8.26-8.20 (m, 2H), 7.40 (d, J=8.3 Hz, 1H), 7.37 (d,J=2.5 Hz, 1H), 7.29 (d, J=9.7 Hz, 1H), 7.14 (dd, J=8.5, 2.4 Hz, 1H),5.42 (dd, J=8.2, 2.2 Hz, 1H), 4.15 (t, J=6.2 Hz, 2H), 3.81-3.53 (m, 3H),2.83 (t, J=7.8 Hz, 2H), 2.61-2.42 (m, 2H), 2.27-2.17 (m, 1H), 2.16-2.09(m, 2H); MS (ESI+): Calc'd for C₂₃H₂₃Cl₂F₃N₅O₂ [M+H]: 528.1, Found:528.8.

tert-butyl(2S,4R)-2-(3-(4-(3-(3,4-dichlorophenyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-4-hydroxypyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 63% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.31 (d, J=2.1 Hz, 1H), 8.18 (dd, J=8.8, 2.1Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.08-7.01 (m,2H), 5.23 (t, J=7.9 Hz, 1H), 4.69-4.64 (m, 1H), 4.08 (t, J=5.9 Hz, 2H),3.82 (dd, J=11.8, 4.3 Hz, 1H), 3.70 (d, J=12.1 Hz, 1H), 2.83 (t, J=7.5Hz, 2H), 2.51-2.46 (m, 1H), 2.34-2.31 (m, 1H), 2.19-2.10 (m, 2H), 1.45(s, 3H), 1.28 (s, 6H).

tert-butyl(((tert-butoxycarbonyl)amino)((2S,4R)-2-(3-(4-(3-(3,4-dichlorophenyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-4-hydroxypyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 44% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.30 (d, J=2.1 Hz, 1H), 8.18 (dd, J=8.7, 2.2 Hz,1H), 7.34 (d, J=8.2 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.06-6.99 (m, 2H),5.84 (t, J=8.3 Hz, 1H), 4.68-4.63 (m, 1H), 4.10-4.03 (m, 3H), 3.76 (d,J=12.0 Hz, 1H), 2.82 (t, J=7.6 Hz, 2H), 2.57 (ddt, J=13.4, 7.7, 2.1 Hz,1H), 2.41-2.33 (m, 1H), 2.19-2.10 (m, 2H), 2.04 (s, 1H), 1.46 (s, 18H).

Example 32:amino((2S,4R)-2-(3-(4-(3-(3,4-dichlorophenyl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-4-hydroxypyrrolidin-1-yl)methaniminiumchloride (Compound 31)

Synthesized by General Procedure E. 100% yield, white solid; ¹H NMR (600MHz, Methanol-d4) δ 8.23 (s, 2H), 7.40 (d, J=7.7 Hz, 1H), 7.36 (s, 1H),7.32-7.27 (m, 1H), 7.14 (d, J=7.8 Hz, 1H), 5.61-5.56 (m, 1H), 4.64-4.61(m, 1H), 4.17-4.14 (m, 2H), 3.92-3.86 (m, 1H), 3.63-3.55 (m, 1H),2.86-2.80 (m, 2H), 2.68-2.62 (m, 1H), 2.55-2.51 (m, 1H), 2.15-2.12 (m,2H); ¹³C NMR (151 MHz, cd₃od) δ 177.87, 167.17, 159.15, 156.22, 142.03,132.67, 131.75, 130.23, 130.15, 129.41, 128.19, 125.77, 118.14, 113.56,68.38, 67.52, 66.74, 55.80, 53.50, 39.70, 30.51, 30.02; MS (ESI+):Calc'd for C₂₃H₂₃Cl₂F₃N₅O₃ [+H]: 544.1, Found: 544.4.

tert-butyl(S)-2-(3-(3-(trifluoromethyl)-4-(3-(4-(trifluoromethyl)phenyl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 62% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.32 (s, 1H), 8.21-8.15 (m, 1H), 7.54 (d,J=7.9 Hz, 3H), 7.32 (d, J=7.9 Hz, 2H), 7.02 (dd, J=13.8, 8.5 Hz, 1H),5.23-5.03 (m, 1H), 4.09 (t, J=5.9 Hz, 2H), 3.76-3.66 (m, 1H), 2.93 (t,J=7.6 Hz, 2H), 2.46-2.34 (m, 1H), 2.22-2.09 (m, 4H), 2.06-1.97 (m, 1H),1.47 (s, 3H), 1.30 (s, 6H).

tert-butyl(S)-(((tert-butoxycarbonyl)amino)(2-(3-(3-(trifluoromethyl)-4-(3-(4-(trifluoromethyl)phenyl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 37% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.31 (d, J=2.1 Hz, 1H), 8.18 (dd, J=8.7, 2.2 Hz,1H), 7.54 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 7.01 (d, J=8.7 Hz,1H), 5.61 (dd, J=7.9, 4.6 Hz, 1H), 4.09 (t, J=5.9 Hz, 2H), 3.94-3.87 (m,1H), 3.80 (s, 1H), 2.93 (t, J=7.5 Hz, 2H), 2.49-2.42 (m, 1H), 2.22-2.14(m, 4H), 2.08-2.01 (m, 1H), 1.46 (s, 18H).

Example 33:(S)-amino(2-(3-(3-(trifluoromethyl)-4-(3-(4-(trifluoromethyl)phenyl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 32A)

Synthesized by General Procedure E. 100% yield, white solid; ¹H NMR (600MHz, Methanol-d4) δ 8.27-8.22 (m, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.41 (d,J=7.9 Hz, 2H), 7.31 (d, J=9.3 Hz, 1H), 5.46 (dd, J=8.0, 1.7 Hz, 1H),4.18 (t, J=5.9 Hz, 2H), 3.82-3.71 (m, 1H), 3.65-3.57 (m, 1H), 2.94 (t,J=7.6 Hz, 2H), 2.63-2.53 (m, 1H), 2.52-2.44 (m, 1H), 2.32-2.03 (m, 4H);MS (ESI+): Calc'd for C₂₄H₂₄F₆N₅O₂ [M+H]: 528.1, Found: 528.6.

tert-butyl(2S,4R)-4-hydroxy-2-(3-(3-(trifluoromethyl)-4-(3-(4-(trifluoromethyl)phenyl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 54% yield, yellow oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.32 (d, J=2.1 Hz, 1H), 8.18 (dd, J=8.7, 2.1Hz, 1H), 7.57-7.52 (m, 2H), 7.32 (d, J=7.9 Hz, 2H), 7.03 (d, J=8.9 Hz,1H), 5.23 (t, J=7.9 Hz, 1H), 4.69-4.63 (m, 1H), 4.09 (t, J=5.9 Hz, 2H),3.82 (dd, J=11.8, 4.3 Hz, 1H), 3.70 (d, J=11.9 Hz, 1H), 2.93 (t, J=7.5Hz, 2H), 2.50-2.47 (m, 1H), 2.34-2.28 (m, 1H), 2.22-2.14 (m, 2H), 1.45(s, 3H), 1.28 (s, 6H).

tert-butyl(((tert-butoxycarbonyl)amino)((2S,4R)-4-hydroxy-2-(3-(3-(trifluoromethyl)-4-(3-(4-(trifluoromethyl)phenyl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. 10% yield, yellow oil; ¹H NMR (600MHz, Chloroform-d) δ 8.31 (d, J=2.1 Hz, 0H), 8.18 (dd, J=8.8, 2.2 Hz,0H), 7.54 (d, J=8.0 Hz, 0H), 7.32 (d, J=8.0 Hz, 0H), 7.02 (d, J=8.7 Hz,0H), 6.01 (s, 0H), 4.66 (s, 0H), 4.12-4.02 (m, 0H), 3.83 (d, J=12.4 Hz,0H), 3.53 (s, 0H), 2.93 (t, J=7.5 Hz, 0H), 2.67-2.60 (m, 0H), 2.47-2.38(m, 1H), 2.22-2.14 (m, 0H), 1.48 (s, 1H).

Example 34:amino((2S,4R)-4-hydroxy-2-(3-(3-(trifluoromethyl)-4-(3-(4-(trifluoromethyl)phenyl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 33A)

Synthesized by General Procedure E. 85% yield, white solid; ¹H NMR (600MHz, Methanol-d4) δ 8.27-8.22 (m, 2H), 7.58 (d, J=2.1 Hz, 8H), 7.42 (d,J=8.1 Hz, 9H), 7.30 (d, J=9.6 Hz, 4H), 5.60-5.55 (m, 1H), 4.65-4.59 (m,1H), 4.18 (t, J=5.9 Hz, 2H), 3.88 (dd, J=10.7, 4.6 Hz, 1H), 3.67-3.56(m, 1H), 2.94 (t, J=7.6 Hz, 2H), 2.70-2.61 (m, 1H), 2.56-2.48 (m, 1H),2.23-2.15 (m, 2H); MS (ESI+): Calc'd for C₂₄H₂₄F₆N₅O₃ [M+H]: 544.2,Found: 544.6.

3-(1-allyl-1H-benzo[d]imidazol-2-yl)propan-1-ol

Synthesized by General Procedure I. 26% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 7.75-7.68 (m, 1H), 7.35-7.20 (m, 3H), 5.99-5.90 (m,1H), 5.25-5.18 (m, 1H), 5.00-4.93 (m, 1H), 4.85-4.72 (m, 2H), 3.81 (t,J=5.5 Hz, 2H), 3.03 (t, J=6.7 Hz, 2H), 2.20-2.12 (m, 2H).

4-(3-(1-allyl-1H-benzo[d]imidazol-2-yl)propoxy)-3-(trifluoromethyl)benzonitrile

Synthesized by General Procedure A. 89% yield, yellow solid; 1H NMR (600MHz, Chloroform-d) δ 7.88-7.83 (m, 1H), 7.80-7.70 (m, 2H), 7.32-7.20 (m,3H), 7.09 (d, J=8.7 Hz, 1H), 5.97-5.87 (m, 1H), 5.20-5.14 (m, 1H),4.96-4.89 (m, 1H), 4.76-4.71 (m, 2H), 4.32 (t, J=5.7 Hz, 2H), 3.08 (t,J=7.3 Hz, 2H), 2.55-2.44 (m, 2H).

tert-butyl(2S,3S)-2-(3-(4-(3-(1-allyl-1H-benzo[d]imidazol-2-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 74% yield, yellow solid; 1HNMR (600 MHz, Chloroform-d) δ 8.28 (s, 1H), 8.18 (t, J=9.7 Hz, 1H), 7.82(d, J=7.0 Hz, 1H), 7.34 (td, J=8.3, 5.4 Hz, 3H), 7.12-7.03 (m, 1H), 5.95(ddt, J=15.7, 10.1, 4.9 Hz, 1H), 5.23 (d, J=10.4 Hz, 1H), 5.02-4.93 (m,2H), 4.82 (dt, J=3.8, 1.8 Hz, 2H), 4.58 (d, J=19.1 Hz, 1H), 4.30 (t,J=6.5 Hz, 2H), 3.81-3.72 (m, 2H), 3.23 (t, J=7.5 Hz, 2H), 2.54 (p, J=6.1Hz, 2H), 2.41-2.28 (m, 1H), 2.09-2.02 (m, 1H), 1.47 (s, 3H), 1.30 (s,6H).

tert-butyl(((2S,3S)-2-(3-(4-(3-(1-allyl-1H-benzo[d]imidazol-2-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate

Synthesized by General Procedure D. 58% yield, yellow solid; 1H NMR (600MHz, Chloroform-d) δ 10.02 (s, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.14 (dd,J=8.7, 2.2 Hz, 1H), 7.77-7.71 (m, 1H), 7.32-7.21 (m, 3H), 7.01 (d, J=8.8Hz, 1H), 5.97-5.88 (m, 1H), 5.52-5.48 (m, 1H), 5.20-5.15 (m, 1H),4.97-4.91 (m, 1H), 4.78-4.73 (m, 2H), 4.65 (s, 1H), 4.25 (t, J=5.5 Hz,2H), 4.04-3.92 (m, 2H), 3.88 (s, 1H), 3.16-3.09 (m, 2H), 2.51-2.43 (m,2H), 2.43-2.34 (m, 1H), 2.18-2.08 (m, 1H), 1.45 (s, 18H).

Example 35:((2S,3S)-2-(3-(4-(3-(1-allyl-1H-benzo[d]imidazol-2-yl)propoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-1-yl)(amino)methaniminiumchloride (Compound 47A)

Synthesized by General Procedure E. 100% yield, yellow solid; 1H NMR(600 MHz, Methanol-d4) δ 8.30 (dd, J=8.7, 2.2 Hz, 1H), 8.23 (d, J=2.1Hz, 1H), 7.88-7.78 (m, 2H), 7.68-7.60 (m, 2H), 7.43 (d, J=8.7 Hz, 1H),6.14-6.04 (m, 1H), 5.37-5.32 (m, 1H), 5.26-5.16 (m, 4H), 4.81-4.76 (m,1H), 4.43 (t, J=5.5 Hz, 2H), 3.87-3.78 (m, 2H), 3.52-3.46 (m, 2H),2.55-2.47 (m, 2H), 2.25-2.15 (m, 2H); MS (ESI+): Calc'd forC₂₇H₃₀F₃N₇O₃[M+2H]: 278.6, Found: 279.2.

4-(nonyloxy)-3-(trifluoromethyl)benzonitrile

Synthesized by General Procedure A. 100% yield, colorless oil; 1H NMR(600 MHz, Chloroform-d) δ 7.83 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.7, 2.1Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 1.92-1.79 (m,2H), 1.50-1.43 (m, 2H), 1.38-1.22 (m, 10H), 0.87 (t, J=7.0 Hz, 3H).

tert-butyl(2S,3S)-3-hydroxy-2-(3-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 77% yield, yellow oil; 1H NMR(600 MHz, Chloroform-d) δ 8.29-8.23 (m, 1H), 8.20-8.12 (m, 1H),7.09-7.01 (m, 1H), 5.12-4.93 (m, 1H), 4.61-4.53 (m, 1H), 4.13-4.06 (m,2H), 3.82-3.68 (m, 2H), 2.39-2.28 (m, 1H), 2.09-2.01 (m, 1H), 1.88-1.80(m, 2H), 1.52-1.44 (m, 5H), 1.39-1.22 (m, 16H), 0.88 (t, J=6.9 Hz, 3H).

tert-butyl(((tert-butoxycarbonyl)imino)((2S,3S)-3-hydroxy-2-(3-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methyl)carbamate

Synthesized by General Procedure D. 60% yield, yellow oil; 1H NMR (600MHz, Chloroform-d) δ 8.26 (d, J=2.1 Hz, 1H), 8.16 (dd, J=8.7, 2.1 Hz,1H), 7.05 (d, J=8.7 Hz, 1H), 5.52 (d, J=2.3 Hz, 1H), 4.64 (s, 1H), 4.10(t, J=6.4 Hz, 2H), 4.06-3.92 (m, 2H), 2.41-2.34 (m, 1H), 2.16-2.09 (m,1H), 1.88-1.80 (m, 2H), 1.45 (s, 18H), 1.40-1.22 (m, 12H), 0.88 (t,J=6.9 Hz, 3H).

Example 36:amino((2S,3S)-3-hydroxy-2-(3-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 64A)

General Procedure E. 100% yield, white solid; 1H NMR (600 MHz,Methanol-d4) δ 8.25-8.18 (m, 2H), 7.31 (d, J=8.7 Hz, 1H), 5.27 (s, 1H),4.79 (d, J=3.7 Hz, 1H), 4.17 (t, J=6.2 Hz, 2H), 3.90-3.79 (m, 2H),2.28-2.15 (m, 2H), 1.87-1.79 (m, 2H), 1.51 (ddd, J=15.2, 8.4, 6.2 Hz,2H), 1.42-1.24 (m, 10H), 0.89 (t, J=6.8 Hz, 3H); 13C NMR (151 MHz,cd₃od) δ 176.96, 168.64, 160.86, 157.54, 133.97, 127.38, 127.05, 125.58,123.77, 121.97, 120.67, 120.52, 120.31, 120.11, 119.19, 114.80, 75.97,70.29, 64.77, 49.43, 49.29, 49.14, 49.00, 48.86, 48.72, 48.57, 47.43,32.99, 32.46, 30.59, 30.28, 30.26, 30.00, 26.87, 23.70, 14.43; MS(ESI+): Calc'd for C₂₃H₃₃F₃N₅O₃ [M+H]: 484.3, Found: 485.2.

tert-butyl(2S,4R)-4-fluoro-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. ¹H NMR (400 MHz, DMSO-d₆) δ8.26-8.15 (m, 2H), 8.10 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 5.51-5.41 (m,1H), 5.35-5.28 (m, 1H), 5.21-5.13 (m, 2H), 4.18 (t, J=6.2 Hz, 2H),3.88-3.70 (m, 3H), 2.76 (s, 3H), 1.75-1.65 (m, 2H), 1.41-1.31 (m, 3H),1.30-1.19 (m, 5H), 1.16 (s, 3H), 0.90-0.76 (m, 3H); Calcd forC₂₆H₃₅F₄N₃O₄Na [M+Na]⁺: 552.2456, Found: 552.2469.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,4R)-4-fluoro-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

General Procedure D. ¹H NMR (500 MHz, Chloroform-d) δ 10.43 (s, 1H),8.22 (d, J=2.1 Hz, 1H), 8.11 (dd, J=8.7, 2.2 Hz, 1H), 7.97-7.93 (m,0.4H), 7.78-7.72 (m, 0.4H), 7.38-7.34 (m, 0.5H), 6.99 (d, J=8.7 Hz, 1H),6.31-6.28 (m, 0.4H), 5.90-5.70 (m, 1H), 5.38-5.18 (m, 1H), 4.31-3.61 (m,4H), 2.81-2.69 (m, 1H), 2.48-2.25 (m, 1H), 1.81-1.71 (m, 2H), 1.51-1.11(m, 30H), 0.88-0.73 (m, 3H).

Example 37:(2S,4R)-4-fluoro-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide2,2,2-trifluoroacetate) (Compound 49A)

Synthesized by General Procedure J. ¹H NMR (400 MHz, Methanol-d₄) δ8.26-8.17 (m, 2H), 7.31 (d, J=8.7 Hz, 1H), 5.66 (t, J=7.9 Hz, 1H), 5.51(s, 0.4H), 5.41 (s, 0.6H), 4.16 (t, J=6.2 Hz, 2H), 4.03-3.89 (m, 2H),3.13-2.94 (m, 1H), 2.75-2.57 (m, 1H), 1.87-1.77 (m, 2H), 1.42-1.20 (m,9H), 0.94-0.79 (m, 3H); ¹³C NMR (101 MHz, cd₃od) δ 177.4, 167.3, 159.5,156.2, 132.4, 126.5, 125.7, 124.6, 117.7, 113.4, 91.5, 89.8, 68.9, 56.3,54.6, 53.0, 46.9, 31.5, 28.6, 25.5, 22.8, 22.3, 17.8, 17.2, 15.8, 13.0;Calcd for C₂₂H₃₀F₄N₅O₂ [M+H]⁺: 472.233, Found: 473.0.

tert-butyl(2S,4S)-4-fluoro-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedure B and C. ¹H NMR (400 MHz, Acetone-d₆) δ8.32-8.18 (m, 2H), 7.40 (dd, J=8.8, 3.9 Hz, 1H), 5.53-5.27 (m, 2H),4.24-4.18 (m, 2H), 3.91-3.61 (m, 2H), 3.05-2.74 (m, 1H), 2.70-2.44 (m,1H), 2.08-2.01 (m, 1H), 1.89-1.79 (m, 2H), 1.64-1.21 (m, 18H), 0.92-0.78(m, 3H)

tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,4S)-4-fluoro-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by General Procedure D. ¹H NMR (400 MHz, Chloroform-d) δ9.98 (s, 1H), 8.25 (d, J=2.1 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.03(d, J=8.7 Hz, 1H), 5.81-5.41 (m, 1H), 5.40-5.35 (m, 0.5H), 5.28-5.21 (m,0.5H), 4.19-3.98 (m, 4H), 2.85-2.71 (m, 1H), 2.69-2.51 (m, 1H),1.91-1.75 (m, 2H), 1.51-1.31 (m, 18H), 1.30-1.21 (m, 9H), 0.94-0.78 (m,3H).

Example 38:(2S,4S)-4-fluoro-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide2,2,2-trifluoroacetate (Compound 48A)

Synthesized by General Procedure J. ¹H NMR (400 MHz, Methanol-d₄) δ8.25-8.14 (m, 2H), 7.30 (d, J=8.7 Hz, 1H), 5.55 (d, J=8.1 Hz, 1H), 4.15(t, J=6.2 Hz, 2H), 4.00-3.85 (m, 2H), 2.97-2.72 (m, 2H), 1.86-1.76 (m,2H), 1.55-1.45 (m, 2H), 1.23-1.41 (m, 8H), 0.93-0.84 (m, 3H); ¹³C NMR(101 MHz, cd₃od) δ 177.6, 167.3, 159.4, 132.5, 125.7, 125.6, 126.0,125.5, 121.9, 118.9, 118.6, 117.9, 113.4, 92.3, 90.5, 68.8, 54.4, 54.2,38.1, 37.9, 31.5, 28.9, 28.8, 28.6, 25.5, 22.3, 13.0. Calcd forC₂₂H₃₀F₄N₅O₂ [M+H]⁺: 472.233, Found: 472.2326.

General procedure A. Nucleophilic aromatic substitution. To aroundbottom, the alkyl alcohol (1 equiv) and potassium tert-butoxide(2.5 equiv) were added and dissolved in THF. The solution was thenrefluxed for 30 minutes. After 30 minutes, the solution was cooled toroom temperature. Once cool, 4-fluorobenzonitrile was added to thereaction and the solution was refluxed for 18 h. Once completion wasobserved, the reaction was cooled to rt. The reaction was thepartitioned between dichloromethane and water. The organic layer wassubsequently washed with brine, dried with sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography to yield the desired product.

General procedure B. Conversion of nitrile to amidoxime. Triethylamine(3.3 equiv) and hydroxylamine hydrochloride (2 equiv) were added to asolution of chosen nitrile intermediate in 95% ethanol (0.2 M solution).The reaction mixture was then refluxed for 2-3 h. The organic solventwas removed under reduced pressure and the residue was purified by flashchromatography on silica gel to provide the desired product.

General procedure C. Coupling of amidoxime with amino acids. DIEA (1.8equiv) was added to a solution of amidoxime (1 equiv) and theappropriate Boc-protected amino acid (1.2 equiv) in DMF (0.2 Msolution). HCTU (1.5 equiv) was then added to the resulting mixture atrt and stirred at 80° C. for 18h. At this time, TLC showed completeconversion of starting material. The solution was partitioned betweenethyl acetate and water. The organic layer was collected and washedtwice with a sat. LiBr. The aqueous solution was then back extractedwith ethyl acetate. The organic layers were then combined and washedwith sat. NaHCO₃ and brine, dried over Na₂SO₄, and concentrated underreduced pressure. The resulting residue was purified by flashchromatography on silica gel to yield the desired product.

General Procedure D: Deprotection of 1-Boc protecting groups using TFA.To a solution of Boc-protected intermediate in CH₂Cl₂, a 1N TFA solutionin CH₂Cl₂ was added. The resulting solution was stirred at roomtemperature until complete consumption of the starting material wasobserved using TLC. The reaction mixture was concentrated under reducedpressure and triturated with diethyl ether to yield the correspondingfree amine TFA salt.

General Procedure E: Guanidylation of amines using the microwave. DIEA(3 equiv) was added to a solution of the corresponding aminehydrochloric acid salt and the reagent (Z)-tert-butyl(((tert-butoxycarbonyl) imino)(1H-pyrazol-1-yl) methyl) carbamate (1.05equiv) in a reaction tube with acetonitrile (20% vol/wt). The resultingreaction mixture was then placed in the microwave reactor and stirredfor 2 hours at 50 degrees Celsius at 200 W. The solvent was then removedunder reduced pressure and the resulting colorless residue was purifiedby flash column chromatography over silica gel to yield the pureproduct.

General Procedure F: Deprotection of t-Boc protecting groups using HClgas. Hydrochloric acid gas was bubbled through a solution of the N-Bocprotected compound in methanol for 2-5 minutes, or until completeconsumption of starting material was observed by TLC. The reactionmixture was concentrated under reduced pressure and triturated withdiethyl ether to yield the corresponding free amine hydrochloride salt,which was further purified by trituration with diethyl ether untilsatisfactory analytical data was obtained.

General procedure G. Williamson ether synthesis with alkyl bromides. Toa roundbottom, 1-bromooctane (1.2 equiv), potassium carbonate (4 equiv),and chosen substituted 4-hydroxybenzonitrile were dissolved in ACN. Thereaction was then refluxed for 18 h. Once the reaction was complete, thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was then washed with brine, dried with sodium sulfate,filtered, and concentrated under reduced pressure. The residue was thenpurified by silica gel column chromatography to yield the desiredproduct.

General procedure H: Suzuki coupling. Chosen alkene (1.1 equiv) wasadded to a round bottom flask containing THF. 9-BBN (1.2 equiv) wasadded as a 0.5 M solution in THF and the solution was stirred overnightat rt. To the above borane solution was added a solution of substitutedor non-substituted 4-iodobenzonitrile in DMF. The reaction mixture wasdegassed for 15 min by bubbling N₂ through the solution. Cs₂CO₃ (2equiv) and PdCl₂ (dppf) (0.03 equiv) were added together. The resultingreaction mixture was then stirred at 80° C. for 18 h, after which it waspoured into a saturated solution of LiBr and extracted three times withhexane. The combined organic extracts were washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure. The resulting brownresidue was purified by flash chromatography over silica gel to give thedesired product.

4-Octyl-3-(trifluoromethyl) benzonitrile. Synthesized by generalprocedure H. 47% yield, yellow oil; ¹H NMR (400 MHz, Chloroform-d) δ7.89 (d, J=1.2 Hz, 1H), 7.74 (dd, J=8.0, 1.6 Hz, 1H), 7.47 (d, J=8.0 Hz,1H), 2.82 (t, J=7.6 Hz, 2H), 1.62 (p, J=8.0 Hz, 2H), 1.39 (p, J=6.8 Hz,2H), 1.35-1.22 (m, 8H), 0.88 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz,Chloroform-d) δ 147.7 (q, ⁴J_(CF)=1.5 Hz), 135.0, 132.1, 129.9 (q,³J_(CF)=5.9 Hz), 129.8 (q, ²J_(CF)=31.2 Hz), 123.5 (q, ¹J_(CF)=276.5Hz), 117.9, 110.3, 33.0 (q, ⁴J_(CF)=1.8 Hz), 31.9, 31.5, 31.5, 29.7,29.4, 29.3, 22.8, 14.2; ¹⁹F NMR (376 MHz, Chloroform-d) δ −63.5 (s, 3F).

(Z)-Hydroxy-4-octyl-3-(trifluoromethyl) benzimidamide

Synthesized by general procedure B. 84% yield, white solid; ¹H NMR (400MHz, Methanol-d₄) δ 7.92 (d, J=1.8 Hz, 1H), 7.78 (dd, J=8.1, 1.5 Hz,1H), 7.44 (d, J=8.1 Hz, 1H), 2.78 (t, J=7.9 Hz, 2H), 1.61 (p, J=8.2 Hz,2H), 1.45-1.24 (m, 10H), 0.89 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz,Methanol-d₄) δ 154.1, 147.7 (q, ⁴J_(CF)=1.4 Hz), 132.5, 132.3, 130.6,130.0, 129.3 (q, ²J_(CF)=29.7 Hz), 128.5 (q, ¹J_(CF)=274.5 Hz), 124.7(q, ³J_(CF)=5.9 Hz), 33.5, 33.0, 32.9, 30.8, 30.5, 30.3, 23.7, 14.4; ¹⁹FNMR (376 MHz, Methanol-d₄) δ −60.5 (s, 3F); HRMS (ESI+): Calcd forC₁₆H₂₄F₃N₂₀ [M+H]: 317.1841, Found: 317.1836.

(S)-Tert-butyl2-(3-(4-octyl-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by general procedure C. 65% yield, yellow oil; ¹H NMR (400MHz, Chloroform-d) δ 8.31 (s, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.44 (t,J=9.3 Hz, 1H), 5.27-5.00 (m, 1H), 3.78-3.63 (m, 1H), 3.60-3.47 (m, 1H),2.81 (t, J=8.2 Hz, 2H), 2.46-2.32 (m, 1H), 2.22-2.08 (m, 2H), 2.08-1.94(m, 1H), 1.63 (p, J=7.3 Hz, 2H), 1.46 (s, 3H), 1.43-1.23 (m, 18H), 0.87(t, J=6.8 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 181.1, 167.6,153.6, 145.3, 131.8, 130.4, 129.3 (q, ²J_(CF)=30.7 Hz), 127.0 (q,¹J_(CF)=274.8 Hz), 125.2 (q, ³J_(CF)=5.8 Hz), 124.9, 124.6, 122.9,110.2, 80.6, 53.9, 46.5, 32.9, 32.5, 32.0, 31.7, 31.6, 29.8, 29.5, 29.3,28.5, 28.3, 24.5, 23.8, 22.8, 14.2; ¹⁹F NMR (376 MHz, Chloroform-d) δ−63.0 (d, J=11.9 Hz, 3F); HRMS (ESI+): Calcd for C₂₆H₃₆F₃N₃O₃Na [M+Na]:518.2606, Found: 518.2594.

(S)-2-(3-(4-Octyl-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-ium2,2,2-trifluoroacetate

Synthesized by general procedure D. 100% conversion, yellow oil; ¹H NMR(400 MHz, Chloroform-d) δ 8.24 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.44 (d,J=8.1 Hz, 1H), 5.19 (t, J=7.8 Hz, 1H), 3.76-3.56 (m, 2H), 2.81 (t, J=7.4Hz, 1H), 2.73-2.64 (m, 1H), 2.51-2.43 (m, 1H), 2.35-2.22 (m, 2H), 1.63(p, J=7.8 Hz, 2H), 1.46-1.20 (m, 10H), 0.88 (t, J=6.8 Hz, 3H); ¹³C NMR(101 MHz, Chloroform-d) δ 174.6, 167.7, 146.2, 131.9, 130.5, 129.4 (q,²J_(CF)=30.7 Hz), 125.3 (q, ³J_(CF)=5.7 Hz), 124.2 (q, ¹J_(CF)=275.1Hz), 123.3, 77.4, 54.3, 46.5, 32.9, 32.0, 31.6, 30.1, 29.8, 29.5, 29.3,24.0, 22.8, 14.2; ¹⁹F NMR (376 MHz, Chloroform-d) δ −60.8 (s, 3F); HRMS(ESI+): Calcd for C₂₁H₂₉F₃N₃O+[M+]: 396.2262, Found: 396.2271.

(S)-Tert-butyl(((tert-butoxycarbonyl)amino)(2-(3-(4-octyl-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by general procedure E. 56% yield, colorless oil; ¹H NMR(400 MHz, Chloroform-d) δ 10.11 (s, 1H), 8.31 (d, J=1.6 Hz, 1H), 8.14(dd, J=8.0, 1.6 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 5.61 (dd, J=7.8, 4.5Hz, 1H), 3.94-3.87 (m, 1H), 3.84-3.75 (m, 1H), 2.81 (t, J=7.1 Hz, 2H),2.50-2.40 (m, 1H), 2.27-2.13 (m, 2H), 2.12-1.98 (m, 1H), 1.63 (p, J=8.8Hz, 2H), 1.51-1.19 (m, 28H), 0.88 (t, J=7.0 Hz, 3H); ¹³C NMR (101 MHz,Chloroform-d) δ 179.5, 167.6, 162.0, 159.4, 153.8, 150.5, 145.3, 131.7,130.5, 129.2 (q, ²J_(CF)=30.5 Hz), 125.4 (q, ³J_(CF)=5.8 Hz), 124.7,124.3 (q, ¹J_(CF)=275.3 Hz), 82.4, 79.7, 55.4, 49.6, 32.9, 32.0, 31.7,29.8, 29.5, 29.3, 28.2, 24.1, 22.8, 14.2; ¹⁹F NMR (376 MHz,Chloroform-d) δ −62.9 (s, 3F); HRMS (ESI+): Calcd for C₃₂H₄₇F₃N₅O₅[M+H]: 638.3529, Found: 638.3507.

Example 39:(S)-Amino(2-(3-(4-octyl-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 5A)

Synthesized by general procedure F. 89% yield, white solid; ¹H NMR (400MHz, Methanol-d₄) δ 8.30 (s, 1H), 8.23 (d, J=7.9 Hz, 1H), 7.62 (d, J=8.0Hz, 1H), 5.60 (d, J=7.6 Hz, 1H), 3.86 (t, J=8.5 Hz, 1H), 3.71 (q, J=9.2Hz, 1H), 2.86 (t, J=8.8 Hz, 2H), 2.70-2.61 (m, 1H), 2.56-2.49 (m, 1H),2.39-2.24 (m, 1H), 2.22-2.07 (m, 1H), 1.68 (p, J=7.6 Hz, 2H), 1.51-1.25(m, 10H), 0.93 (t, J=6.5 Hz, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ179.4, 168.5, 157.1, 146.6, 133.3, 131.7, 129.9 (q, ²J_(CF)=30.3 Hz),125.7, 125.7 (q, ³J_(CF)=5.9 Hz), 125.6 (q, ¹J_(CF)=274.7 Hz), 56.4,49.1, 33.7, 32.9, 32.7, 30.7, 30.4, 30.3, 24.3, 23.6, 14.4; ¹⁹F NMR (376MHz, Methanol-d₄) δ −60.6 (s, 3F); HRMS (ESI+): Calcd forC₂₂H₃₁F₃N₅O+[M+]: 438.2481, Found: 438.2484.

3-Fluoro-4-(octyloxy)benzonitrile

Synthesized by general procedure G. 99% yield, yellow oil; ¹H NMR (400MHz, Chloroform-d) δ 7.39-7.32 (m, 1H), 7.31-7.26 (m, 1H), 6.97 (t,J=8.4 Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 1.80 (p, J=6.6 Hz, 2H), 1.43 (p,J=7.0 Hz, 2H), 1.37-1.17 (m, 8H), 0.84 (t, J=6.6 Hz, 3H); ¹³C NMR (101MHz, Chloroform-d) δ 151.8 (d, ¹J_(CF)=251.1 Hz), 151.4 (d, ²J_(CF)=10.3Hz), 129.6 (d, ³J_(CF)=3.8 Hz), 119.4 (d, ²J_(CF)=21.5 Hz), 118.0 (d,³J_(CF)=2.4 Hz), 114.4 (d, ³J_(CF)=2.6 Hz), 103.5 (d, ²J_(CF)=8.3 Hz),69.5, 31.7, 29.2, 29.1, 28.8, 25.8, 22.6, 14.0; ¹⁹F NMR (376 MHz,Chloroform-d) δ −134.5-134.6 (m, 1F).

(Z)-3-Fluoro-N′-hydroxy-4-(octyloxy)benzimidamide

Synthesized by general procedure B. 44% yield, white solid; ¹H NMR (400MHz, Methanol-d₄) δ 7.39-7.36 (m, 1H), 7.35 (t, J=2.5 Hz, 1H), 7.03 (t,J=8.7 Hz, 1H), 4.02 (t, J=6.4 Hz, 2H), 1.76 (p, J=7.6 Hz, 2H), 1.45 (p,J=6.4 Hz, 2H), 1.37-1.22 (m, 8H), 0.88 (t, J=7.2 Hz, 3H); ¹³C NMR (101MHz, Methanol-d₄) δ 154.2 (d, ³J_(CF)=2.2 Hz), 153.4 (d, ¹J_(CF)=245.7Hz), 149.7 (d, ²J_(CF)=10.9 Hz), 126.8 (d, ³J_(CF)=6.8 Hz), 123.4 (d,³J_(CF)=3.6 Hz), 115.3 (d, ³J_(CF)=2.2 Hz), 114.8 (d, ²J_(CF)=20.6 Hz),70.3, 33.0, 30.4, 30.4, 30.2, 27.0, 23.7, 14.5; ¹⁹F NMR (376 MHz,Chloroform-d) δ −135.8-135.9 (m, 1F); HRMS (ESI+): Calcd forC₁₅H₂₄FN₂O₂[M+H]: 283.1822, Found: 283.1825.

(S)-Tert-butyl2-(3-(3-fluoro-4-(octyloxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by general procedure C. 38% yield, yellow oil; ¹H NMR (400MHz, Chloroform-d) δ 7.81-7.81 (m, 2H), 7.01 (t, J=8.5 Hz, 1H),5.27-4.95 (m, 1H), 4.07 (t, J=6.6 Hz, 2H), 3.74-3.63 (m, 1H), 3.59-3.43(m, 1H), 2.47-2.28 (m, 1H), 2.21-2.06 (m, 2H), 2.05-1.95 (m, 1H), 1.83(p, J=8.0 Hz, 2H), 1.50-1.41 (m, 5H), 1.40-1.21 (m, 14H), 0.87 (t, J=7.0Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 180.7, 167.5 (d, ³J_(CF)=2.6Hz), 154.4, 152.5 (d, ¹J_(CF)=247.9 Hz), 153.6, 149.9 (d, ²J_(CF)=10.5Hz), 124.0 (d, ³J_(CF)=3.5 Hz), 119.3 (d, ²J_(CF)=7.7 Hz), 115.3 (d,²J_(CF)=20.7 Hz), 114.4, 80.6, 69.5, 53.9, 46.4, 32.5, 31.9, 31.6, 29.8,29.4, 29.3, 29.2, 28.5, 28.2, 26.0, 24.5, 23.8, 22.8, 14.2; ¹⁹F NMR (376MHz, Chloroform-d) δ −136.7 (dt, J=11.8, 9.7 Hz, 1F); HRMS (ESI+): Calcdfor C₂₅H₃₆FN₃O₄Na [M+Na]: 484.2588, Found: 484.2622.

(S)-2-(3-(3-Fluoro-4-(octyloxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-ium2,2,2-trifluoroacetate

Synthesized by general procedure D. 100% conversion, white solid; ¹H NMR(400 MHz, Methanol-d₄) δ 7.82 (ddd, J=8.6, 2.0, 1.3 Hz, 1H), 7.74 (dd,J=11.8, 2.1 Hz, 1H), 7.19 (t, J=8.5 Hz, 1H), 5.15 (t, J=7.7 Hz, 1H),4.09 (t, J=6.4 Hz, 2H), 3.65-3.39 (m, 2H), 2.68-2.58 (m, 1H), 2.43-2.34(m, 1H), 2.30-2.12 (m, 2H), 1.79 (p, J=6.4 Hz, 2H), 1.47 (p, J=7.9 Hz,2H), 1.41-1.09 (m, 8H), 0.87 (t, J=6.8 Hz, 3H); ¹³C NMR (126 MHz,Methanol-d₄) δ 176.0, 168.8, 153.7 (d, ¹J_(CF)=246.7 Hz), 151.6 (d,²J_(CF)=10.6 Hz), 125.4 (d, ³J_(CF)=3.6 Hz), 119.6 (d, ²J_(CF)=7.4 Hz),115.9 (d, ²J_(CF)=20.9 Hz), 115.8, 70.4, 55.5, 47.3, 32.9, 30.4, 30.3,30.2, 30.1, 27.0, 24.5, 23.7, 14.4; ¹⁹F NMR (376 MHz, Methanol-d₄) δ−135.1 (dd, J=11.4, 8.4 Hz, 1F); HRMS (ESI+): Calcd for C₂₀H₂₉FN₃O₂+[M+]: 362.2244, Found: 362.2254.

(S)-Tert-butyl(((tert-butoxycarbonyl)amino)(2-(3-(3-fluoro-4-(octyloxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

Synthesized by general procedure E. 44% yield, colorless oil; ¹H NMR(400 MHz, Chloroform-d) δ 10.10 (s, 1H), 7.87-7.65 (m, 2H), 7.01 (d,J=8.5 Hz, 1H), 5.58 (dd, J=7.8, 4.5 Hz, 1H), 4.08 (t, J=6.6 Hz, 2H),3.92-3.84 (m, 1H), 3.80 (s, 1H), 2.48-2.38 (m, 1H), 2.27-2.13 (m, 2H),2.09-1.98 (m, 1H), 1.84 (p, J=7.3 Hz, 2H), 1.55-1.22 (m, 28H), 0.88 (t,J=6.7 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 179.1, 167.5, 162.0,152.5 (d, ¹J_(CF)=247.6 Hz), 150.5, 149.9 (d, ²J_(CF)=10.5 Hz), 124.1(d, ³J_(CF)=3.0 Hz), 119.4, 115.5 (d, ²J_(CF)=20.8 Hz), 114.4, 82.4,79.7, 69.5, 55.4, 49.8, 31.9, 31.4, 29.8, 29.4, 29.3, 29.2, 28.2, 26.0,24.1, 22.8, 14.2; ¹⁹F NMR (376 MHz, Chloroform-d) δ −136.7 (s, 1F); HRMS(ESI+): Calcd for C₃₁H₄₇FN₅O₆ [M+H]: 604.3512, Found: 604.3534.

Example 40:(S)-Amino(2-(3-(3-fluoro-4-(octyloxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (Compound 11A)

Synthesized by general procedure F. 100% conversion, white solid; ¹H NMR(400 MHz, Methanol-d₄) δ 7.81 (d, J=8.2 Hz, 1H), 7.73 (dd, J=11.8, 1.7Hz, 1H), 7.21 (t, J=8.5 Hz, 1H), 5.43 (d, J=6.4 Hz, 1H), 4.12 (t, J=6.3Hz, 2H), 3.77 (t, J=8.4 Hz, 1H), 3.61 (q, J=7.4 Hz, 1H), 2.56 (s, 1H),2.50-2.42 (m, 1H), 2.21 (s, 1H), 2.08 (s, 1H), 1.82 (p, J=6.5 Hz, 2H),1.50 (p, J=7.0 Hz, 2H), 1.43-1.25 (m, 8H), 0.90 (t, J=7.2 Hz, 3H); ¹³CNMR (101 MHz, Methanol-d₄) δ 179.0, 168.7, 157.0, 153.6 (d,¹J_(CF)=247.1 Hz), 151.4 (d, ²J_(CF)=10.6 Hz), 125.3 (d, ³J_(CF)=3.6Hz), 119.9 (d, ²J_(CF)=7.4 Hz), 115.8 (d, ³J_(CF)=2.1 Hz), 115.7 (d,²J_(CF)=20.9 Hz), 70.4, 56.5, 32.9, 32.7, 30.4, 30.4, 30.2, 27.0, 24.3,23.7, 14.4; ¹⁹F NMR (376 MHz, Methanol-d₄) δ −135.1 (dd, J=11.7, 8.4 Hz,1F); HRMS (ESI+): Calcd for C₂₁H₃₁FN₅O₂+[M+]: 404.2462, Found: 404.2449.

General Procedures I. General Procedure for Sonogashira Coupling

Dissolved aryl halide (1.0 equiv) in dry DMF and subjected to degassingwith a gaseous mixture of (H₂+N₂) balloon for three times. AddedPdCl₂(PPh₃)₂ (10 mol %) followed by CuI (8 mol %) at r.t. Added terminalalkyne (1.0 equiv. followed by TEA. The reaction mixture stirred at 50°C. or 90° C. After cooling to room temperature, the resulting solutionwas subjected to rotary evaporation and partitioned between EtOAc andD.I. water. Aqueous layer was extracted with EtOAc 20 mL (3×). Combinedorganic layers were given water, brine washes and dried over anhydrousNa₂SO₄. After evaporation of the solvent, column chromatography onsilica gel afforded the desired product.

II. General Procedure for Chemo Selective Reduction of Alkyne

Dissolved the internal alkyne intermediate in EtOAc (30 mL) at r.t.Added Lindlar's catalyst [(5% Pd-CaCO₃+Pb(OCOCH₃)₂+Quinoline), 10 mol%]. Subjected to hydrogenation under H₂ atmosphere for 30 min to 20 h.Filtered the reaction over Celite bed. Concentrated the filterate andsubjected to column chromatography on silica gel afforded the desiredsaturated product.

III. General Procedure for Synthesis of Amidoxime

Nitrile intermediate (1 equiv.), hydroxylamine hydrochloride (3 equiv.),TEA (3 equiv.) were added to a round bottom flask containing ethanol.The reaction mixture was heated to 80° C. for 6-12 hours and monitoredvia TLC. Once the starting material was consumed, the solution wascooled to room temperature, concentrated under reduced pressure, loadedonto celite, and purified on a silica column with hexane and ethylacetate.

IV. General Procedure for Synthesis of 1,2,4-Oxadiazole

Amidoxime intermediate (1 equiv.), Boc-L-proline (1.4 equiv.) orBoc-trans-3-hydroxy-L-proline (1.4 equiv.), and DIEA (1.4 equiv.) wereadded to a round bottom flask containing DMF. HCTU (1.8 equiv.) wasadded to the reaction mixture and maintained at 110° C. for 12-16 hours.Cooled the reaction mixture to r.t. and partitioned between ethylacetate and saturated LiBr solution. The combined organic layers werewashed with sat. NaHCO₃, brine and dried over sodium sulfate. Combinedorganic layers were subjected to rotary evaporation and columnchromatography to afford the desired Oxadiazole intermediate.

V. General Procedure for Ester Hydrolysis

Dissolved Pyrrolidine acetate in a solution of THF:MeOH (2:3) at r.t.Added 1M LiOH and continued stirring at r.t. for 30 min. Rotaryevaporated the reaction mixture and partitioned between Dichloromethane(20 mL) and water (5 mL). Extracted the aqueous layer usingDichloromethane (10 mL, 2×). Combined organic layers were given brinewash and dried over anhydrous Na₂SO₄. Rotary evaporated the organiclayer and subjected to column chromatography to afford the desiredalcohol.

VI. General Procedure for O-Alkylation

(1 equiv.), potassium carbonate (2 equiv.), KI (1.5 equiv.) and alkylhalide (1.2 equiv.) were added to a 8 mL microwave reactor containingacetone. The reaction mixture was heated to 80° C. for 4-12 hours untilTLC indicated the starting material had been fully consumed. Thereaction mixture was extracted with ethyl acetate and D.I. water. Thecombined organic layers were washed with brine and dried over sodiumsulfate. After filtration and concentration via reduced pressure, theresulting brown oil was purified on a silica column with hexane andethyl acetate.

VII. General Procedure for Boc-Deprotection

N-Boc Pyrrolidine or N′, N″-Di-Boc-guanidine 6a-e was dissolved inmethanol. HCl gas was bubbled into the solution for 1 minute. Thesolution was stirred until TLC indicated that all of the Boc-protectedamine had been consumed. The solvent was removed under reduced pressure.The resulting white to light yellow solid was washed with diethyl etherto yield pure product as HCl salt.

VIII. General Procedure for Guanylation of Secondary Amines

Pyrrolidine Hydrogen chloride salt (1 equiv.) was added to a 8 mLmicrowave reaction flash with acetonitrile and DIEA (3 equiv.). Thesolution was allowed to stir for 10 minutes before the addition of(Z)-Tert-butyl(((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (1.05equiv.). The solution was subjected to microwave irradiation at 55° C.for 2-6 h until TLC indicated that the starting material had beenconsumed. The reaction mixture is subjected to rotary evaporation andperformed column chromatography to afford the N′,N′-diboc guanidineintermediate.

IX. General Procedure for O-Alkylation

To a pre-cooled solution of N-Boc Pyrrolidine alcohol in dry THF added(65%) NaH. Stirred for 10 min. and added excess alkyl halide. Maintainedat 0° C. for 1 h and allowed to attain r.t. Stirred at r.t. for 18-24 h.Quenched reaction mixture at 0° C. with few drops of methanol andcrushed ice. Partitioned reaction mixture between ethyl acetate andwater. The Organic layer is subjected to rotatory evaporation andperformed column chromatography to afford O-alkylated intermediate.

X. General Procedure for Mitsunobu Reaction

To a pre-cooled solution of 23 in dry THF and PPh₃ added DIAD (40% intoluene) and alcohol. The reaction mixture was stirred for 1 h thenrefluxed for 2 h. Quenched reaction mixture with aqueous NaHCO₃, rotaryevaporated and partitioned between dichloromethane and DI water.Combined organic layers were subjected to rotatory evaporation andperformed column chromatography to afford the desired product.

4-(tert-butoxy)-3-(trifluoromethyl)benzonitrile (20)

¹H NMR (500 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.73 (dd, J=8.8, 2.1 Hz,1H), 7.27 (d, J=8.7 Hz, 1H), 1.56 (s, 9H).

(Z)-4-(tert-butoxy)-N′-hydroxy-3-(trifluoromethyl)benzimidamide (21)

¹H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J=2.3 Hz, 1H), 7.72 (dd,J=8.7, 2.4 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 6.72 (s, 1H), 4.84 (s, 2H),1.52 (s, 9H).

tert-butyl(S)-2-(3-(4-(tert-butoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(22)

¹H NMR (500 MHz, Chloroform-d) δ 8.21 (d, J=2.1 Hz, 1H), 8.05 (dd,J=8.6, 2.2 Hz, 1H), 7.20 (t, J=8.6 Hz, 1H), 5.15-5.05 (m, 0.4H),5.04-4.95 (m, 0.6H), 3.71-3.55 (m, 1H), 3.53-3.31 (m, 1H), 2.31-2.21 (m,1H), 2.15-2.05 (m, 2H), 1.99-1.83 (m, 1H), 1.39 (s, 3H), 1.24 (s, 6H).

tert-butyl(S)-2-(3-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(23)

¹H NMR (400 MHz, Methanol-d₄) δ 8.16 (d, J=2.1 Hz, 1H), 8.10-8.04 (m,1H), 7.07 (d, J=8.7 Hz, 1H), 5.16-5.08 (m, 1H), 3.70-3.61 (m, 1H),3.55-3.48 (m, 1H), 2.53-2.36 (m, 1H), 2.20-2.00 (m, 3H), 1.46 (s, 3H),1.27 (s, 6H); ¹³C NMR (101 MHz, cd₃od) δ 181.0, 167.2, 154.0, 131.9,125.8, 124.9, 117.2, 117.0, 80.5, 53.8, 46.1, 31.8, 31.0, 27.2, 26.9,23.9, 23.3.

tert-butyl(S)-2-(3-(4-(4-acetoxybutoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(24)

¹H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 8.17 (d, J=8.7 Hz, 1H),7.05 (d, J=8.8 Hz, 1H), 5.21-5.05 (m, 0.4H). 5.08-5.01 (m, 0.6H),4.16-4.10 (m, 4H), 3.76-3.61 (m, 1H), 3.60-3.41 (m, 1H), 2.45-2.25 (m,1H), 2.24-1.78 (m, 10H), 1.44 (s, 3H), 1.27 (s, 6H); ¹³C NMR (101 MHz,cdcl₃) δ 180.8, 180.3, 171.1, 167.2, 158.9, 153.4, 137.9, 132.4, 126.5,124.5, 118.7, 112.8, 103.3, 80.4, 68.2, 63.8, 53.7, 46.6, 46.3, 32.3,31.4, 28.1, 25.6, 25.0, 23.7, 20.9; Calcd for C₂₄H₃₁F₃N₃O₆ [M+H]⁺:514.2172, Found: 514.2159.

(S,E)-4-(4-(5-(1-(N,N′-bis(tert-butoxycarbonyl)carbamimidoyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)phenoxy)butylacetate (25)

¹H NMR (400 MHz, Chloroform-d) δ 10.08 (s, 1H), 8.26 (s, 1H), 8.16 (d,J=10.8 Hz, 1H), 7.58 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 5.58 (d, J=4.5 Hz,1H), 4.12 (t, J=6.3 Hz, 3H), 3.86 (s, 1H), 3.77 (d, J=5.9 Hz, 1H),2.49-2.36 (m, 1H), 2.21-2.18 (m, 2H), 2.08-1.95 (s, 4H), 1.96-1.80 (m,4H), 1.46 (s, 18H); ¹³C NMR (101 MHz, cdcl₃) δ 179.2, 171.1, 167.1,158.9, 132.5, 126.8, 126.7, 124.5, 118.7, 112.7, 105.0, 68.2, 63.8,55.2, 49.4, 29.7, 28.0, 28.0, 25.6, 25.1, 20.9; Calcd for C₃₀H₄₁F₃N₅O₈[M+H]⁺: 658.2959, Found: 658.2971.

4-bromo-N′-hydroxy-3-(trifluoromethyl)benzimidamide (14)

¹H NMR (400 MHz, Methanol-d₄) δ 8.07-8.02 (m, 1H), 7.84-7.79 (m, 1H),7.78-7.73 (m, 1H); Calcd for C₈H₇F₃BrN₂O [M+H]⁺: 282.9688, Found:282.9696.

tert-butyl(S)-2-(3-(4-bromo-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(15)

¹H NMR (400 MHz, Methanol-d₄) δ 8.37 (d, J=2.0 Hz, H), 8.16 (t, J=7.0Hz, 1H), 7.99 (t, J=7.5 Hz, 1H), 5.21-5.12 (m, 1H), 3.71-3.61 (m, 1H),3.56-3.48 (m, 1H), 2.55-2.39 (m, 1H), 2.23-1.99 (m, 3H), 1.42 (s, 4H),1.27 (s, 5H); ¹³C NMR (101 MHz, cdcl₃) δ 181.5, 166.8, 154.3, 153.4,135.7, 131.4, 127.0, 126.7, 126.3, 126.3, 126.3, 123.9, 123.2, 123.2,122.9, 121.2, 80.6 53.8, 46.6, 46.4, 32.4, 31.5, 28.3 28.1, 24.4, 23.7.

4-(cyclopropylethynyl)-3-(trifluoromethyl)benzonitrile (2a)

¹H NMR (500 MHz, Chloroform-d) δ 7.82-7.78 (m, 1H), 7.64 (dd, J=8.1, 1.7Hz, 1H), 7.54-7.49 (m, 1H), 1.48-1.40 (m, 1H), f0.95-0.87 (m, 2H),0.86-0.78 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 135.6, 135.2, 133.9,133.8, 132.4, 132.1, 131.9, 131.6, 129.0, 128.9, 128.9, 128.9, 126.8,126.8, 126.8, 126.8, 125.1, 122.9, 120.8, 118.6, 116.8, 110.0, 105.4,79.5, 76.6, 70.5, 60.3, 8.6, 8.1, −0.6

4-(cyclopentylethynyl)-3-(trifluoromethyl)benzonitrile (2b)

¹H NMR (400 MHz, Chloroform-d) δ 7.87-7.84 (m, 1H), 7.69 (dd, J=8.1, 1.7Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 2.93-2.81 (m, 1H), 2.04-1.89 (m, 2H),1.82-1.66 (m, 4H), 1.67-1.51 (m, 2H); ¹³C NMR (101 MHz, cdcl₃) δ 136.2,134.5, 134.5, 134.4, 134.4, 133.1, 132.8, 132.4, 132.1, 129.5, 129.4,129.4, 129.3, 127.5, 127.5, 127.5, 127.5, 126.5, 123.8, 121.1, 118.3,117.3, 110.7, 106.8, 106.8, 106.8, 77.3, 77.2, 77.0, 76.7, 75.5, 33.5,33.5, 33.3, 33.2, 33.2, 30.9, 29.7, 25.1, 25.0, 25.0; HRMS (ESI+): Calcdfor C₁₅H₁₂F₃N [M+Na]: 286.2475

4-(cyclohex-1-en-1-ylethynyl)-3-(trifluoromethyl)benzonitrile (2c)

¹H NMR (400 MHz, Chloroform-d) δ 7.87-7.85 (m, 1H), 7.72-7.67 (m, 1H),7.60-7.56 (m, 1H), 6.34-6.28 (m, 1H), 2.30-1.99 (m, 4H), 1.76-1.50 (m,4H); ¹³C NMR (101 MHz, cdcl₃) δ 139.0, 138.0, 134.5, 134.1, 132.6,132.3, 132.0, 131.7, 131.3, 129.6, 129.5, 129.5, 129.5, 129.4, 127.0,126.5, 123.8, 122.6, 121.1, 120.5, 120.2, 119.9, 118.4, 118.4, 117.8,117.3, 110.8, 110.3, 102.3, 102.2, 83.3, 82.7, 82.0, 28.7, 26.0, 22.0,21.2.

4-((4-propylphenyl)ethynyl)-3-(trifluoromethyl)benzonitrile (2d)

¹H NMR (500 MHz, Methanol-d₄) δ 8.18-8.15 (m, 1H), 8.01 (dd, J=8.1, 1.2Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.51-7.46 (m, 2H), 7.31-7.26 (m, 2H),2.69-2.64 (m, 2H), 1.71-1.61 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); ¹³C NMR(101 MHz, cd₃od) δ 187.5, 145.0, 135.2, 134.3, 131.4, 128.5, 127.7,37.6, 24.0, 12.6.

4-((4-methoxyphenyl)ethynyl)-3-(trifluoromethyl)benzonitrile (2e)

¹H NMR (400 MHz, Chloroform-d) δ 7.93 (dt, J=1.4, 0.7 Hz, 1H), 7.77-7.73(m, 1H), 7.70 (dt, J=8.1, 0.7 Hz, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.49 (d,J=2.1 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 3.84 (s,3H); ¹³C NMR (101 MHz, cdcl₃) δ 160.8, 134.6, 134.0, 133.6, 132.3,129.6, 129.6, 129.5, 126.9, 123.9, 121.2, 117.4, 114.3, 113.7, 110.9,100.6, 83.4, 55.4.

3-(trifluoromethyl)-4-((4-(trifluoromethyl)phenyl)ethynyl)benzonitrile(2f)

¹H NMR (500 MHz, Chloroform-d) δ 8.02 (dt, J=1.4, 0.7 Hz, 1H), 7.88-7.80(m, 2H), 7.72-7.66 (m, 4H).

4-(2-cyclopropylethyl)-3-(trifluoromethyl)benzonitrile (3a)

¹H NMR (400 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.76-7.71 (m, 1H), 7.47(d, J=8.1 Hz, 1H), 2.99-2.92 (m, 0.6H), 2.91-2.79 (m, 1.4H), 1.69-1.57(m, 1H), 1.57-1.49 (m, 1H), 1.43-1.32 (m, 3H), 0.95-0.87 (m, 2H),0.50-0.45 (m, 1H), 0.10-s 0.03 (m, 1H); ¹³C NMR (101 MHz, cdcl₃) δ191.4, 147.5, 134.8, 134.7, 132.2, 132.0, 129.9, 129.8, 129.8, 129.8,129.8, 124.7, 122.0, 117.7, 110.2, 110.2, 58.9, 36.5, 33.1, 33.0, 32.8,32.8, 32.8, 31.7, 31.0, 22.3, 13.9, 10.8, 4.6.

4-(2-cyclopentylethyl)-3-(trifluoromethyl)benzonitrile (3b)

¹H NMR (400 MHz, Chloroform-d) δ 7.90 (dt, J=1.8, 0.6 Hz, 1H), 7.77-7.70(m, 1H), 7.47 (dq, J=8.1, 0.6 Hz, 1H), 2.88-2.78 (m, 2H), 1.91-1.76 (m,3H), 1.69-1.50 (m, 6H), 1.20-1.08 (m, 2H); ¹³C NMR (101 MHz, cdcl₃) δ147.7, 134.8, 134.7, 132.0, 130.1, 129.9, 129.8, 129.7, 129.5, 129.2,124.7, 122.0, 117.7, 110.1, 40.2, 40.1, 38.4, 38.0, 36.3, 36.2, 36.1,35.0, 32.9, 32.7, 32.6, 32.5, 32.4, 32.3, 32.2, 29.1, 25.2, 25.1.

4-(4-methoxyphenethyl)-3-(trifluoromethyl)benzonitrile (3d)

¹H NMR (400 MHz, Chloroform-d) δ 7.92 (dt, J=1.4, 0.6 Hz, 1H), 7.70 (dd,=8.0, 1.7 Hz, 1H), 7.36 (dt, J=8.0, 0.7 Hz, 1H), 7.14-7.04 (m, 4H),3.14-3.05 (m, 2H), 2.92-2.84 (m, 2H), 2.60-2.48 (m, 3H), 1.69-1.52 (m,3H), 0.93 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, cdcl₃) δ 146.1, 140.9,137.4, 134.8, 132.4, 129.9, 129.9, 128.7, 128.2, 117.6, 110.5, 37.6,37.0, 35.2, 35.1, 24.6, 13.8.

4-(4-methoxyphenethyl)-3-(trifluoromethyl)benzonitrile (3e)

¹H NMR (400 MHz, Chloroform-d) δ 7.96-7.90 (m, 1H), 7.71 (dd, J=8.0, 1.8Hz, 1H), 7.36 (dd, J=8.1, 0.8 Hz, 1H), 7.13-7.05 (m, 2H), 6.87-6.79 (m,2H), 3.80 (s, 3H), 3.15-3.07 (m, 2H), 2.91-2.82 (m, 2H); ¹³C NMR (101MHz, cdcl₃) δ 158.2, 157.6, 146.1, 146.0, 146.0, 134.8, 134.8, 134.7,132.6, 132.4, 132.2, 130.5, 130.0, 130.0, 129.9, 129.9, 129.8, 129.7,129.4, 129.2, 127.5, 124.7, 122.0, 119.3, 117.6, 114.0, 113.9, 113.7,110.6, 55.3, 55.2, 36.5, 36.5, 35.3, 35.3, 35.3, 35.3, 34.9, 31.2.

3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethyl)benzonitrile (3f)

¹H NMR (400 MHz, Chloroform-d) δ 7.95-7.93 (m, 1H), 7.75-7.72 (m, 1H),7.57-7.51 (m, 2H), 7.38-7.36 (m, 1H), 7.31-7.25 (m, 2H), 3.14 (dd,J=9.7, 6.6 Hz, 2H), 2.96 (dd, J=10 Hz, 6.3 Hz, 2H).

4-(4-butylphenethyl)-3-(trifluoromethyl)benzonitrile (3g)

1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J=1.7 Hz, 1H), 7.70 (dd,J=8.0, 1.7 Hz, 1H), 7.38-7.32 (m, 1H), 7.13-7.02 (m, 4H), 3.11 (dd,J=9.7, 6.7 Hz, 2H), 2.91-2.81 (m, 2H), 2.63-2.51 (m, 2H), 1.63-1.50 (m,2H), 1.40-1.27 (m, 2H), 0.91 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, cdcl₃)δ 146.2, 146.2, 146.1, 143.2, 141.1, 137.4, 136.2, 135.9, 134.9, 132.4,130.3, 130.0, 130.0, 129.9, 129.8, 129.8, 129.7, 129.4, 129.2, 128.7,128.5, 128.3, 127.6, 124.9, 124.1, 122.1, 119.4, 117.6, 110.6, 60.4,37.1, 35.4, 35.3, 35.2, 35.2, 35.2, 35.1, 33.7, 33.4, 29.8, 29.4, 22.4,14.2, 14.0, 13.9

4-(2-cyclopropylethyl)-N′-hydroxy-3-(trifluoromethyl)benzimidamide (4a)

¹H NMR (400 MHz, Chloroform-d) δ 9.83 (s, 1H), 7.88 (d, J=1.6 Hz, 1H),7.70 (dt, J=8.0, 2.3 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.01 (s, 2H),2.93-2.71 (m, 2H), 1.71-1.45 (m, 2H), 1.41-1.28 (m, 1H), 1.02-0.79 (m,2H), 0.57-0.38 (m, 1H), 0.11-0.03 (m, 1H); ¹³C NMR (101 MHz, cdcl₃) δ151.9, 151.9, 143.7, 143.7, 143.7, 143.7, 143.3, 143.3, 143.3, 143.3,131.6, 131.4, 131.3, 130.1, 130.0, 129.1, 129.1, 129.0, 129.0, 128.9,128.9, 128.9, 128.8, 128.8, 128.5, 128.5, 128.4, 128.2, 128.2, 125.7,125.7, 123.6, 123.6, 123.6, 123.5, 123.5, 123.5, 123.5, 122.9, 120.2,36.7, 32.7, 32.6, 32.6, 32.6, 32.5, 32.5, 32.5, 32.4, 31.8, 31.2, 29.7,22.5, 22.4, 14.0, 13.9, 10.9, 10.8, 4.5, 4.4; Calcd for C13H16F3N20[M+H]⁺: 273.1209, Found: 273.121.

4-(2-cyclopentylethyl)-N′-hydroxy-3-(trifluoromethyl)benzimidamide (4b)

¹H NMR (400 MHz, Methanol-d₄) δ 7.92 (d, J=1.9 Hz, 1H), 7.77 (dd, J=8.1,2.0 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 2.84-2.74 (m, 2H), 1.92-1.71 (m,3H), 1.70-1.45 (m, 6H), 1.16-1.12 (m, 2H); ¹³C NMR (101 MHz, cd₃od) δ152.6, 143.1, 143.0, 140.6, 140.1, 137.9, 131.7, 131.3, 131.2, 131.1,130.8, 129.2, 129.2, 129.2, 129.1, 129.1, 128.7, 128.6, 128.3, 128.0,127.7, 127.4, 127.0, 125.9, 123.4, 123.3, 123.2, 123.0, 120.5, 43.9,40.1, 40.0, 38.2, 32.5, 32.3, 32.2, 31.5, 31.5, 24.7

(E)-4-(cyclohex-1-en-1-ylethynyl)-N′-hydroxy-3-(trifluoromethyl)benzimidamide(4c)

¹H NMR (400 MHz, Methanol-d₄) δ 7.97 (dq, J=1.9, 0.6 Hz, 1H), 7.81 (ddq,=8.1, 1.8, 0.6 Hz, 1H), 7.57 (dp, J=8.1, 0.7 Hz, 1H), 6.24 (tt, J=3.8,1.7 Hz, 1H), 2.25-2.14 (m, 4H), 1.75-1.60 (m, 4H).

N′-hydroxy-4-(4-methoxyphenethyl)-3-(trifluoromethyl)benzimidamide (4e)

¹H NMR (400 MHz, Methanol-d₄) δ 7.93 (d, J=1.9 Hz, 1H), 7.74 (dd, J=8.4,2.0 Hz, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.07 (dd, J=5.9, 3.3 Hz, 2H),6.86-6.77 (m, 2H), 3.07-2.96 (m, 2H), 2.82 (dd, J=9.9, 5.8 Hz, 2H); ¹³CNMR (101 MHz, cd₃od) δ 158.2, 152.6, 141.7, 132.9, 131.5, 131.1, 129.0,129.0, 128.6, 128.1, 127.8, 125.9, 123.4, 123.3, 123.3, 123.2, 123.2,113.4, 54.2, 47.8, 47.8, 47.6, 47.6, 47.4, 47.3, 47.1, 47.1, 46.9, 46.9,36.6, 34.7, 34.7, 34.7.

N′-hydroxy-3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethyl)benzimidamide(4f)

¹H NMR (500 MHz, Methanol-d₄) δ 7.99 (d, J=1.9 Hz, 1H), 7.86-7.78 (m,1H), 7.63-7.56 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.45-7.35 (m, 2H),3.20-3.11 (m, 2H), 3.03 (dd, J=9.9, 6.2 Hz, 2H).

4-(4-butylphenethyl)-N′-hydroxy-3-(trifluoromethyl)benzimidamide (4g)

¹H NMR (400 MHz, Methanol-d₄) δ 8.00-7.98 (m, 0.4H), 7.98-7.96 (m,0.4H), 7.93-7.91 (m, 0.6H), 7.77-7.73 (m, 0.6H), 7.46 (d, J=8.1 Hz,0.5H), 7.42-7.38 (m, 0.6H), 3.12-3.01 (m, 2H), 2.89-2.80 (m, 2H),2.59-2.53 (m, 2H), 1.61-1.51 (m, 2H), 1.39-1.26 (m, 2H), 0.92 (t, J=7.3Hz, 3H); ¹³C NMR (101 MHz, cd₃od) δ 147.4, 140.5, 138.1, 131.5, 129.1,128.1, 127.9, 125.1, 37.1, 36.9, 34.8, 33.6, 21.9, 12.8.

4-((4-ethylphenyl)ethynyl)-N′-hydroxy-3-(trifluoromethyl)benzimidamide(8)

¹³C NMR (101 MHz, cd₃od) δ 187.5, 154.5, 151.9, 145.7, 133.5, 132.8,131.2, 131.0, 130.7, 128.8, 127.8, 124.9, 123.3, 123.2, 123.1, 122.2,122.2, 122.2, 119.5, 119.5, 96.0, 96.0, 83.9, 83.9, 28.4, 14.4

tert-butyl(S)-2-(3-(4-((4-ethylphenyl)ethynyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(9)

¹H NMR (400 MHz, Chloroform-d) δ 8.38 (d, J=1.7 Hz, 1H), 8.19 (dd,J=8.0, 1.9 Hz, 1H), 7.72 (t, J=8.2 Hz, 1H), 7.49-7.40 (m, 2H), 7.20-7.15(m, 2H), 5.21-5.15 (m, 0.4H), 5.08-5.01 (m, 0.6H), 3.75-3.61 (m, 1H),3.61-3.41 (m, 1H), 2.64 (q, J=7.6 Hz, 2H), 2.45-2.26 (m, 1H), 2.21-2.06(m, 2H), 2.05-1.92 (m, 1H), 1.44 (s, 3H), 1.25 (s, 6H), 1.21 (t, J=7.6Hz, 3H); ¹³C NMR (101 MHz, cdcl₃) δ 181.5, 181.3, 180.8, 180.8, 167.0,166.7, 154.3, 153.4, 14 5.8, 145.8, 145.6, 135.7, 135.5, 134.1, 134.0,133.8, 132.5, 132.2, 132.1, 131.9, 131.8, 131.7, 131.6, 131.4, 131.2,130.0, 129.7, 128.3, 128.0, 128.0, 127.4, 127.3, 126.7, 126.3, 126.0,125.1, 124.9, 124.9, 124.7, 124.6, 124.3, 121.8, 119.4, 119.1, 97.8,97.6, 97.1, 84.7, 84.6, 84.5, 80.5, 80.4, 53.8, 53.7, 46.6, 46.3, 38.0,32.4, 31.4, 28.9, 28.3, 28.1, 24.4, 23.7, 15.3; Calcd for C₃₆H₄₇F₃N₅O₅[M+H]⁺: 686.3524, Found 686.3522.

tert-butyl(S)-2-(3-(4-((4-(tert-butyl)phenyl)ethynyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(12)

¹H NMR (400 MHz, Chloroform-d) δ 8.39-8.36 (m, 1H), 8.20 (d, J=8.1 Hz,1H), 7.74 (t, J=8.4 Hz, 1H), 7.52-7.47 (m, 2H), 7.42-7.35 (m, 2H),5.21-5.15 (m, 0.4H), 5.11-5.03 (m, 0.6H), 3.76-3.62 (m, 1H), 3.61-3.43(m, 2H), 2.47-2.28 (m, 2H), 2.02 (dq, J=11.0, 7.2, 5.7 Hz, 1H), 1.45 (s,4H), 1.35-1.24 (m, 17H).

tert-butyl(S)-2-(3-(4-(2-cyclopropylethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5a)

¹H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 1H), 8.15-8.06 (m, 1H),7.46-7.38 (m, 1H), 5.25-5.13 (m, 0.3H), 5.09-4.99 (m, 0.7H), 3.74-3.61(m, 1H), 3.59-3.41 (m, 1H), 2.92 (t, J=8.1 Hz, 0.5H), 2.79 (t, J=8.1 Hz,1.5H), 2.48-2.28 (m, 1H), 2.21-2.05 (m, 2H), 2.04-1.99 (m, 1H),1.65-1.58 (m, 1H), 1.56-1.18 (m, 12H), 0.93-0.84 (m, 2H), 0.47-0.40 (m,1H), 0.07-0.01 (m, 1H); ¹³C NMR (101 MHz, cdcl₃) δ 171.1, 167.7, 166.7,156.9, 153.9, 152.2, 150.8, 149.9, 147.6, 142.5, 134.9, 134.8, 131.9,129.8, 122.2, 120.4, 119.6, 116.0, 115.8, 115.0, 114.9, 114.1, 113.8,110.0, 105.9, 104.8, 69.7, 62.6, 60.4, 56.8, 56.4, 56.3, 56.1, 56.0,56.0, 55.9, 51.9, 34.8, 30.8, 30.6, 29.9, 29.6, 21.4, 21.0, 19.0, 18.9,18.8, 14.1, 14.1, 13.8; HRMS (ESI+): Calcd for C₂₃H₂₈F₃N₃O₃Na [M+Na]⁺:474.1975, Found: 474.1986.

tert-butyl(S)-2-(3-(4-(2-cyclopentylethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5b)

¹H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 1H), 8.12 (d, J=8.0 Hz, 1H),7.41 (dd, J=16.9, 6.4 Hz, 1H), 5.05 (dd, J=8.1, 3.6 Hz, 1H), 3.75-3.57(m, 1H), 3.56-3.38 (m, 1H), 2.88-2.75 (m, 2H), 2.47-2.27 (m, 1H),2.21-2.08 (m, 2H), 2.07-1.92 (m, 1H), 1.93-1.72 (m, 3H), 1.68-1.49 (m,4H), 1.44 (s, 3H), 1.28 (s, 6H), 1.19-1.09 (m, 1H); ¹³C NMR (101 MHz,cdcl₃) δ 181.0, 167.4, 153.5, 131.7, 130.3, 124.4, 110.0, 80.5, 53.8,46.3, 40.2, 38.2, 33.0, 32.5, 32.4, 32.1, 31.5, 28.3, 28.1, 25.2, 25.2,23.7.

tert-butyl(2S,3S)-2-(3-(4-(2-cyclopentylethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidine-1-carboxylate(5bA)

¹H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 1H), 8.13 (d, J=8.4 Hz, 1H),7.44 (s, 1H), 4.97 (s, 1H), 4.59 (s, 1H), 3.85-3.65 (m, 2H), 2.83 (t,J=8.3 Hz, 2H), 2.41-2.12 (m, 1H), 2.10-1.99 (m, 1H), 1.95-1.75 (m, 3H),1.71-1.38 (m, 9H), 1.31 (s, 6H), 1.22-1.07 (m, 2H); ¹³C NMR (101 MHz,cdcl₃) δ 191.4, 178.6, 167.6, 153.6, 151.1, 131.9, 131.7, 130.3, 125.1,124.2, 80.9, 77.1, 76.1, 75.1, 62.5, 62.2, 44.7, 44.3 44.0, 40.2, 38.2,33.8, 33.0, 32.5, 32.2, 32.1, 29.7, 28.3, 28.1, 25.5, 25.2.

tert-butyl(S)-2-(3-(4-(2-(cyclohex-1-en-1-yl)ethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5c)

¹H NMR (400 MHz, Chloroform-d) δ 8.36-8.27 (m, 1H), 8.19-8.09 (m, 1H),7.41-7.29 (m, 1H), 5.44-5.38 (m, 0.4H), 5.21-5.13 (m, 0.6H), 5.08-5.01(m, 1H), 3.78-3.42 (m, 3H), 2.97-2.72 (m, 2H), 2.44-2.28 (m, 1H),2.27-1.92 (m, 6H), 1.86-1.40 (m, 9H), 1.37-1.04 (m, 8H), 0.94-0.82 (m,1H); ¹³C NMR (101 MHz, cdcl₃) δ 191.3, 181.0, 180.5, 167.4, 154.3,153.5, 145.6, 144.8, 141.5, 136.5, 131.8, 131.7, 131.4, 130.4, 130.3,130.2, 130.0, 125.5, 125.1, 124.6, 124.5, 123.1, 122.8, 122.0, 117.8,80.5, 53.8, 46.6, 46.3, 41.4, 39.8, 39.5, 37.9, 37.2, 37.2, 35.4, 33.2,32.8, 32.6, 32.4, 31.4, 30.3, 29.9, 29.7, 28.8, 28.5, 28.3, 28.3, 28.1,27.7, 26.8, 26.6, 26.3, 26.0, 25.9, 25.8, 25.5, 25.2, 24.3, 23.7, 22.9,22.4.

tert-butyl(S)-2-(3-(4-(4-propylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5d)

¹H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J=1.6 Hz, 1H), 8.14 (d, J=7.7Hz, 1H), 7.39 (dd, J=17.8, 8.1 Hz, 1H), 3.61 (d, J=82.5 Hz, 3H), 3.12(t, J=8.2 Hz, 2H), 2.97-2.87 (m, 2H), 2.61-2.53 (m, 2H), 2.41 (s, 2H),2.16 (s, 2H), 2.08-1.96 (m, 1H), 1.70-1.58 (m, 2H), 1.51-1.40 (m, 3H),1.31 (s, 6H), 0.95 (t, J=7.3 Hz, 3H); ¹³C NMR (101 MHz, cdcl₃) δ 191.4,181.0, 167.4, 153.5, 143.9, 143.9, 140.6, 138.1, 132.0, 132.0, 130.3,130.3, 128.6, 128.3, 125.2, 5d80.5, 53.8, 46.6, 46.4, 37.6, 37.4, 35.1,32.4, 28.4, 28.1, 24.6, 23.7, 13.8.

tert-butyl(S)-2-(3-(4-(4-butylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5g)

¹H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1H), 8.13 (d, J=7.5 Hz, 1H),7.38 (dd, J=18.8, 8.0 Hz, 1H), 7.11 (d, J=3.0 Hz, 4H), 5.23-5.15 (m,0.4H), 5.09-5.03 (m, 0.6H), 3.80-3.65 (m, 1H), 3.63-3.44 (m, 1H), 3.10(t, J=8.2 Hz, 2H), 2.88 (dd, J=10.4, 6.2 Hz, 2H), 2.58 (t, J=7.7 Hz,2H), 2.48-2.31 (m, 1H), 2.21-2.05 (m, 2H), 2.09-1.95 (m, 1H), 1.63-1.53(m, 2H), 1.45 (s, 3H), 1.32-1.21 (m, 6H), 0.91 (t, J=7.3 Hz, 3H); ¹³CNMR (101 MHz, cdcl₃) δ 181.0, 167.4, 143.9, 143.6, 140.8, 138.0, 132.0,131.9, 130.3, 128.5, 128.3, 124.9, 80.5, 53.8, 46.6, 46.4, 37.4, 35.2,35.1, 35.1, 33.7, 32.4, 31.5, 28.4, 28.1, 24.4, 23.7, 22.3, 22.3, 13.9;Calcd for C₃₀H₃₆F₃N₃O₃Na [M+Na]⁺: 566.2601, Found: 566.2602.

tert-butyl(2S,3S)-2-(3-(4-(4-butylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidine-1-carboxylate(5gA)

¹H NMR (400 MHz, Chloroform-d) δ 8.35-8.28 (m, 1H), 8.15-8.05 (m, 1H),7.85-7.75 (m, 1H), 7.44-7.29 (m, 1H), 7.11 (d, J=2.4 Hz, 4H), 5.14-5.11(m, 0.4H), 4.99-4.95 (m, 0.6H), 4.63-4.53 (m, 1H), 3.83-3.67 (m, 2H),3.18-3.05 (m, 2H), 2.91-2.81 (m, 2H), 2.62-2.52 (m, 2H), 2.39-2.21 (m,2H), 2.10-2.01 (m, 2H), 1.64-1.51 (m, 2H), 1.47 (s, 3H), 1.40-1.21 (m,6H), 0.91 (t, J=7.3 Hz, 3H); ¹³C NMR (101 MHz, cdcl₃) δ 178.7, 167.5,144.1, 140.9, 138.0, 132.0, 131.9, 130.3, 128.5, 128.3, 126.8, 125.2,124.6, 81.1, 76.0, 75.0, 62.5, 62.3, 44.9, 44.4, 37.4, 35.2, 35.1, 33.7,32.5, 32.2, 28.4, 28.1, 22.3, 13.9; Calcd for C₃₀H₃₀F₃N₃O₄Na [M+Na]⁺:582.255, Found: 582.2511.

tert-butyl(2S,3S)-3-hydroxy-2-(3-(4-(4-propylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5dA)

¹H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.13 (d, J=8.4 Hz, 1H),7.45-7.35 (m, 1H), 7.13 (s, 4H), 5.15-5.08 (m, 0.4H), 4.98 (s, 0.6H),4.65-4.55 (m, 1H), 3.91-3.61 (m, 2H), 3.18-3.09 (m, 2H), 2.95-2.82 (m,2H), 2.62-2.48 (m, 2H), 2.45-2.25 (m, 1H), 2.09-2.01 (m, 1H), 1.74-1.55(m, 2H), 1.48 (s, 3H), 1.32 (s, 6H), 0.95 (t, J=7.3 Hz, 3H); ¹³C NMR(101 MHz, cdcl₃) δ 191.4, 181.1, 167.4, 153.5, 143.9, 140.6, 138.1,132.0, 130.3, 128.6, 128.3, 125.6, 125.2, 124.9, 80.5, 53.8, 46.6, 46.4,37.6, 37.4, 35.1, 32.4, 31.5, 28.4, 28.1, 24.6, 24.4, 23.7, 13.8; Calcdfor C₂₉H₃₄F₃N₃ONa [M+Na]⁺: 568.2394, Found: 568.2376.

tert-butyl(S)-2-(3-(4-(4-(tert-butyl)phenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5h)

¹H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.16 (d, J=7.7 Hz, 1H),7.51-7.38 (m, 1H), 7.35 (m, 2H), 7.24-7.13 (m, 2H), 5.25-5.18 (m, 0.4H),5.11-5.04 (m, 0.6H), 3.79-3.61 (m, 1H), 3.60-3.42 (m, 1H), 3.20-3.07 (m,2H), 2.95-2.85 (m, 2H), 2.49-2.31 (m, 1H), 2.21-1.91 (m, 2H), 1.47 (s,3H), 1.33 (m, 9H), 1.30 (s, 6H); ¹³C NMR (126 MHz, CDCl₃) δ 181.1,167.4, 153.5, 149.2, 144.0, 137.9, 132.0, 130.4, 129.0, 128.1, 126.9,125.8, 125.4, 125.2, 80.5, 77.3, 77.2, 77.0, 76.7, 53.8, 46.6, 46.4,37.3, 35.0, 34.4, 32.4, 31.4, 31.2, 31.2, 29.7, 28.4, 28.2, 27.6, 24.4,23.7, Calcd for C₃₀H₃₆F₃N₃O₃Na [M+Na]⁺: 569.2691, Found: 569.2712.

tert-butyl(S)-2-(3-(4-(4-methoxyphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5e)

¹H NMR (500 MHz, Chloroform-d) δ 8.38 (d, J=2.3 Hz, 1H), 8.19-8.11 (m,1H), 7.39 (dd, J=25.4, 7.8 Hz, 1H), 7.19-7.10 (m, 2H), 6.91-6.83 (m,2H), 5.23 (dd, J=8.4, 2.7 Hz, 0.4H), 5.10 (dd, J=8.2, 3.8 Hz, 0.6H),3.79-3.67 (m, 1H), 3.60 (dt, J=10.0, 7.0 Hz, 1H), 3.12 (dt, J=10.1, 5.6Hz, 2H), 2.95-2.85 (m, 2H), 2.24-2.11 (m, 2H), 2.10-1.99 (m, 1H), 1.49(s, 3H), 1.33 (s, 6H); ¹³C NMR (101 MHz, cdcl₃) δ 181.0, 180.6, 177.7,172.2, 171.9, 167.3, 165.6, 162.4, 158.1, 154.4, 154.2, 153.7, 153.4,143.8, 143.5, 132.9, 132.0, 131.9, 130.3, 129.3, 129.1, 125.6, 125.2,125.1, 124.9, 122.8, 113.9, 113.8, 80.4, 56.4, 56.3, 55.2, 53.8, 46.7,46.6, 46.5, 46.3, 38.5, 36.9, 36.8, 36.4, 35.2, 35.2, 35.2, 32.4, 31.4,31.3, 30.3, 29.5, 28.5, 28.4, 28.3, 28.2, 28.1, 24.3, 24.1, 23.7, 23.6;Calcd for C₂₇H₃₀F₃N₃O₄Na [M+Na]⁺: 542.2141, Found: 542.2141.

tert-butyl(2S,3S)-3-hydroxy-2-(3-(4-(4-methoxyphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5eA)

¹H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J=14.4 Hz, 1H), 8.10 (dd,J=17.9, 8.1 Hz, 1H), 7.42-7.29 (m, 1H), 7.17-7.07 (m, 2H), 6.89-6.81 (m,2H), 5.14 (s, 0H), 4.98 (d, J=2.0 Hz, 0H), 4.63-4.51 (m, 1H), 3.79 (s,4H), 3.10 (dd, J=10.2, 6.0 Hz, 2H), 2.87 (t, J=8.3 Hz, 2H), 2.34 (tt,J=8.9, 4.9 Hz, 1H), 2.13-2.01 (m, 1H), 1.48 (s, 3H), 1.38-1.21 (m, 5H);¹³C NMR (101 MHz, cdcl₃) δ 178.7, 178.2, 167.5, 158.1, 154.7, 153.8,144.0, 143.8, 132.9, 132.1, 131.9, 131.8, 130.5, 130.3, 129.5, 129.4,129.2, 128.3, 125.5, 125.2, 125.2, 124.8, 124.6, 122.8, 113.9, 113.7,81.0, 80.9, 76.0, 75.0, 62.5, 62.3, 60.5, 55.3, 55.1, 44.9, 44.4, 36.8,36.6, 35.2, 32.5, 32.2, 29.7, 28.4, 28.1, 24.7, 23.4, 14.1.

tert-butyl(S)-2-(3-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate (5f)

¹H NMR (400 MHz, Chloroform-d) δ 8.37 (d, J=1.7 Hz, 1H), 8.16 (d, J=7.7Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.36 (dd, J=31.3, 8.0 Hz, 3H),5.28-5.03 (m, 1H), 3.84-3.46 (m, 2H), 3.15 (t, J=8.2 Hz, 2H), 3.00 (dd,J=10.1, 6.2 Hz, 2H), 2.54-2.32 (m, 1H), 2.27-1.93 (m, 3H), 1.47 (s, 3H),1.31 (s, 6H); ¹³C NMR (101 MHz, cdcl₃) δ 181.2, 167.3, 153.4, 144.9,143.0, 131.9, 130.5, 128.8, 128.5, 125.5, 125.5, 125.4, 125.4, 80.5,77.2, 53.8, 46.6, 46.3, 37.4, 34.6, 32.4, 31.5, 28.3, 28.1, 24.4, 23.7.

tert-butyl(2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5hA)

¹H NMR (400 MHz, Chloroform-d) δ 8.35 (d, J=9.8 Hz, 1H), 8.14 (t, J=9.5Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.36 (dd, J=32.7, 7.9 Hz, 3H), 5.13 (s,0.3H), 4.98 (s, 0.7H), 4.65-4.55 (m, 1H), 3.86-3.68 (m, 2H), 3.15 (t,J=8.4 Hz, 2H), 2.98 (dd, J=15.2, 7.9 Hz, 2H), 2.45-2.21 (m, 2H),2.15-2.03 (m, 1H), 1.48 (s, 3H), 1.32 (s, 6H);

¹³C NMR (101 MHz, cdcl₃) δ 178.9, 178.3, 167.3, 155.4, 151.2, 144.8,131.9, 130.4, 128.7, 125.4, 125.4, 125.0, 80.9, 75.9, 65.8, 62.5, 62.3,44.9, 44.4, 37.4, 34.6, 32.5, 32.2, 28.3, 28.1, 21.0, 15.2, 14.1.

tert-butyl(S)-2-(3-(4-(4-ethylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5i)

¹H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.13 (s, 1H), 7.45-7.31(m, 1H), 7.13 (s, 4H), 5.23-5.16 (m, 0.4H), 5.11-5.03 (m, 0.6H),3.79-3.62 (m, 1H), 3.62-3.42 (m, 1H), 3.11 (t, J=8.2 Hz, 2H), 2.94-2.83(m, 2H), 2.62 (q, J=7.6 Hz, 2H), 2.45-2.31 (m, 1H), 2.18-2.08 (m, 2H),2.05-1.95 (m, 1H), 1.46 (s, 3H), 1.30 (m, 6H), 1.23 (t, J=7.6 Hz, 3H);¹³C NMR (101 MHz, cdcl₃) δ 181.0, 180.6, 167.4, 154.3, 153.5, 143.9,143.6, 142.2, 138.1, 135.7, 132.0, 1318, 131.6, 131.4, 130.3, 130.1,129.4, 129.1, 128.3, 128.0, 127.9, 125.5, 125.2, 125.1, 125.1, 124.9,122.8, 80.5, 53.8, 53.7, 46.6, 46.3, 38.1, 37.4, 35.1, 35.1, 32.4, 31.5,29.7, 28.4, 28.3, 28.1, 24.4, 23.7, 15.6; Calcd for C₂₈H₃₂F₃N₃O₃Na[M+Na]⁺: 538.2288, Found: 538.2309.

tert-butyl(S,E)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(2-cyclopropylethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6a)

¹H NMR (400 MHz, Chloroform-d) δ 10.09 (s, 1H), 8.31 (d, J=1.7 Hz, 1H),8.14 (dt, J=8.2, 2.5 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 5.61 (dd, J=7.8,4.5 Hz, 1H), 3.96-3.69 (m, 2H), 2.95-2.89 (m, 0.7H), 2.85-2.75 (m,1.3H), 2.51-2.40 (m, 1H), 2.25-2.19 (m, 1H), 2.08-1.95 (m, 1H),1.69-1.55 (m, 2H), 1.55-1.30 (m, 18H), 0.48-0.42 (m, 1H), 0.075-0.035(m, 1H); ¹³C NMR (101 MHz, cdcl₃) δ 179.4, 167.4, 145.1, 144.7, 131.8,131.5, 130.4, 130.3, 129.5, 129.2, 128.9, 128.6, 128.3, 125.5, 125.3,125.2, 125.1, 124.5, 122.8, 120.1, 55.3, 49.4, 36.7, 32.9, 32.7, 32.7,31.8, 31.2, 29.7, 28.1, 28.0, 24.0, 22.4, 13.9, 10.9, 4.6.

tert-butyl(S,E)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(2-cyclopentylethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6b)

¹H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=1.7 Hz, 1H), 8.14 (dd,J=8.0, 1.8 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 5.61 (dd, J=7.8, 4.5 Hz,1H), 3.95-3.75 (m, 2H), 2.87-2.79 (m, 2H), 1.92-1.76 (m, 3H), 1.70-1.37(m, 22H), 1.16 (dd, J=13.1, 6.0 Hz, 9H), 0.87 (dt, J=9.7, 6.3 Hz, 2H).

Tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,3S)-2-(3-(4-(2-cyclopentylethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-1-yl)methylene)carbamate(6bA)

¹H NMR (400 MHz, Chloroform-d) δ 10.03 (s, 1H), 8.30 (d, J=1.7 Hz, 1H),8.13 (dd, J=7.9, 1.8 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 5.54-5.49 (m, 1H),4.63 (s, 1H), 4.10-3.88 (m, 2H), 2.88-2.79 (m, 2H), 2.66-2.41 (m, 1H),2.40-2.32 (m, 1H), 2.15-2.05 (m, 1H), 1.92-1.75 (m, 2H), 1.69-1.36 (m,20H), 1.34-1.09 (m, 6H); ¹³C NMR (101 MHz, cdcl₃) δ 191.3, 177.1, 167.5,158.4, 150.8, 145.5, 131.7, 130.4, 129.2, 128.9, 125.5, 125.3, 125.2,124.3, 122.8, 63.3, 46.9, 40.2, 38.1, 32.6, 32.1, 29.7, 28.1, 28.0,25.2, 25.2, 22.7.

tert-butyl(S,E)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(2-(cyclohex-1-en-1-yl)ethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6c)

¹H NMR (400 MHz, Chloroform-d) δ 10.07 (s, 1H), 8.43-8.03 (m, 2H), 7.41(d, J=7.5 Hz, 1H), 5.64 (s, 1H), 3.88 (s, 2H), 2.81 (s, 1H), 2.47 (s,1H), 2.13 (d, J=57.4 Hz, 3H), 1.90-0.59 (m, 25H).

tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,3S)-2-(3-(4-(4-butylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-1-yl)methylene)carbamate(6gA)

¹H NMR (400 MHz, Chloroform-d) δ 9.99 (s, 1H), 8.33 (d, J=1.7 Hz, 1H),8.12 (dd, J=8.0, 1.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.12 (s, 4H), 5.53(d, J=2.3 Hz, 1H), 4.68-4.61 (m, 1H), 4.08-3.90 (m, 2H), 3.14-3.06 (m,2H), 2.94-2.84 (m, 2H), 2.63-2.55 (m, 2H), 2.41-2.25 (m, 1H), 2.24-2.07(m, 1H), 1.65-1.53 (m, 3H), 1.54-1.16 (m, 20sH), 0.98-0.81 (m, 3H); ¹³CNMR (101 MHz, cdcl₃) δ 177.2, 167.4, 153.9, 144.0, 140.8, 138.0, 131.9,130.4, 129.4, 129.1, 128.5, 128.3, 125.4, 125.3, 124.7, 77.2, 74.8,63.3, 46.9, 45.8, 37.3, 35.2, 35.1, 35.0, 33.7, 32.0, 29.7, 28.1, 22.3,14.1, 13.9, 8.6; Calcd for C₃₆H₄₇F₃N₅O₆ [M+H]⁺: 704.3533, Found:704.3527.

tert-butyl(S,E)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(4-propylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6d)

¹H NMR (400 MHz, Chloroform-d) δ 10.4-9.8 (brs, 1H), 8.35 (d, J=1.7 Hz,1H), 8.13 (dd, J=8.0, 1.8 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.12 (s, 4H),5.62 (dd, J=7.8, 4.5 Hz, 1H), 4.02-3.70 (m, 2H), 3.12 (dd, J=10.1, 6.4Hz, 2H), 3.00-2.80 (m, 2H), 2.65-2.43 (m, 3H), 2.27-2.15 (m, 2H),2.11-1.94 (m, 1H), 1.69-1.57 (m, 2H), 1.51-1.31 (m, 18H), 0.94 (t, J=7.3Hz, 3H); ¹³C NMR (101 MHz, cdcl₃) δ 179.4, 167.4, 153.7, 143.8, 140.6,138.1, 131.9, 130.4, 128.6, 128.3, 125.4, 125.3, 124.9, 82.3, 79.6,77.2, 55.3, 49.5, 37.6, 37.4, 35.1, 35.1, 28.1, 24.6, 24.0, 13.8; Calcdfor C₃₆H₄₇F₃N₅O₅ [M+H]⁺: 686.3524, Found: 686.3522.

Tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,3S)-3-hydroxy-2-(3-(4-(4-propylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6dA)

¹H NMR (400 MHz, Chloroform-d) δ 8.34 (d, J=1.6 Hz, 1H), 8.12 (dd,J=7.9, 1.6 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.12 (s, 4H), 5.56 (s, 1H),4.61 (s, 1H), 4.10-3.92 (m, 2H), 3.16-3.08 (m, 2H), 2.95-2.85 (m, 2H),2.85-2.61 (brs, 1H), 2.57 (dd, J=8.3, 7.0 Hz, 2H), 2.45-2.34 (m, 1H),2.21-2.05 (m, 1H), 1.71-1.58 (m, 2H), 1.47 (s, 18H), 0.94 (t, J=7.3 Hz,3H); NMR (101 MHz, cdcl₃) δ 179.4, 167.4, 153.7, 143.8, 140.6, 138.1,131.9, 131.6, 130.4, 129.6, 129.3, 129.0, 128.7, 128.6, 128.3, 125.6,125.4, 125.4, 125.3, 125.3, 124.9, 122.8, 120.1, 82.3, 79.6, 55.3, 49.5,37.6, 37.4, 35.1, 35.1, 35.1, 35.0, 31.2, 29.7, 28.1, 28.0, 27.8, 24.6,24.0, 13.8; Calcd for C₃₆H₄₇F₃N₅O₆ [M+H]⁺: 702.3473, Found: 704.3482.

Tert-butyl(S,E)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(4-butylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6g)

¹H NMR (400 MHz, Chloroform-d) δ 8.34-8.32 (m, 1H), 8.14-8.08 (m, 1H),7.36 (d, J=8.1 Hz, 1H), 7.10 (s, 4H), 5.65-5.55 (m, 1H), 3.95-3.85 (m,1H), 3.85-3.73 (m, 2H), 3.15-3.05 (m, 2H), 2.91-2.83 (m, 2H), 2.61-2.54(m, 1H), 2.49-2.39 (m, 1H), 2.25-2.10 (m, 2H), 2.08-1.97 (m, 1H),1.61-1.31 (s, 23H), 0.96-0.80 (m, 3H); ¹³C NMR (101 MHz, cdcl₃) δ 179.4,167.3, 158.3, 153.6, 143.8, 140.8, 138.0, 131.9, 131.8, 130.4, 129.6,129.3, 129.0, 128.7, 128.5, 128.3, 125.6, 125.4, 125.3, 125.3, 125.2,124.9, 122.8, 81.3, 55.3, 49.4, 37.3, 35.2, 35.1, 35.0, 33.7, 31.9,31.4, 29.7, 29.3, 28.3, 28.2, 28.1, 28.0, 28.0, 27.9, 24.0, 22.6, 22.3,14.1, 13.9; Calcd for C₃₆H₄₇F₃N₅O₅ [M+H]⁺: 686.3524, Found: 686.3522.

Tert-butyl(S,E)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(4-methoxyphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6e)

¹H NMR (400 MHz, Chloroform-d) δ 10.10 (s, 2H), 8.35 (d, J=1.7 Hz, 1H),8.13 (dd, J=8.0, 1.8 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.15-7.07 (m, 2H),6.88-6.81 (m, 2H), 5.62 (dd, J=7.8, 4.5 Hz, 1H), 3.91 (dt, J=11.5, 7.1Hz, 1H), 3.80 (d, J=0.5 Hz, 4H), 3.10 (dd, J=9.9, 6.5 Hz, 2H), 2.92-2.81(m, 2H), 2.45 (dt, J=13.2, 7.7 Hz, 1H), 2.21 (q, J=6.6 Hz, 2H),2.12-1.95 (m, 1H), 1.58-1.30 (m, 18H); ¹³C NMR (101 MHz, cd₃od) δ 175.5,163.4, 158.0, 154.1, 149.8, 146.4, 139.8, 129.0, 128.0, 126.4, 125.7,125.4, 125.4, 125.1, 124.8, 124.4, 121.6, 121.5, 121.4, 121.4, 121.3,121.0, 118.9, 110.0, 110.0, 109.8, 78.4, 75.6, 51.3, 45.5, 32.9, 32.7,31.3, 24.1, 20.7, 20.1.

Tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,3S)-3-hydroxy-2-(3-(4-(4-methoxyphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6eA)

¹H NMR (400 MHz, Chloroform-d) δ 10.25-9.89 (brs, 1H), 8.31 (d, J=1.5Hz, 1H), 8.10 (dd, J=8.0, 1.5 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.14-7.05(m, 2H), 6.86-6.79 (m, 2H), 5.52 (d, J=1.7 Hz, 1H), 4.62 (s, 1H),4.07-3.89 (m, 2H), 3.78 (s, 3H), 3.44-3.03 (m, 3H), 2.85 (dd, J=9.7, 6.5Hz, 2H), 2.43-1.31 (m, 1H), 2.17-2.07 (m, 1H), 1.44 (s, 18H); ¹³C NMR(101 MHz, cdcl₃) δ 177.4, 167.3, 153.8, 144.8, 144.8, 143.0, 135.6,131.9, 131.6, 131.5, 130.5, 129.7, 129.4, 129.2, 129.1, 128.9, 128.8,128.8, 128.7, 128.6, 128.3, 128.2, 128.2, 127.2, 125.6, 125.5, 125.5,125.5, 125.4, 125.4, 125.0, 122.9, 122.7, 120.2, 120.0, 77.3, 77.2,77.0, 76.7, 74.8, 63.3, 46.9, 37.4, 34.6, 32.0, 29.7, 28.0, 28.0.

tert-butyl(S,E)-(((tert-butoxycarbonyl)amino)(2-(3-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6f)

¹³C NMR (101 MHz, cdcl₃) δ 179.5, 167.2, 153.7, 144.8, 142.8, 131.8,130.5, 129.4, 129.1, 128.8, 125.6, 125.5, 125.5, 125.5, 125.4, 125.4,125.3, 82.3, 79.6, 77.2, 55.3 49.5, 37.4, 34.6 31.3, 28.1, 28.0 24.1.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6fA)

¹H NMR (400 MHz, Chloroform-d) δ 9.95 (s, 2H), 8.34 (d, J=1.7 Hz, 1H),8.14 (dd, J=8.0, 1.8 Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.1 Hz,1H), 7.31 (d, J=8.0 Hz, 2H), 5.54 (d, J=2.3 Hz, 1H), 4.64 (dt, J=5.1,2.9 Hz, 1H), 4.06-3.91 (m, 2H), 3.14 (dd, J=10.0, 6.3 Hz, 2H), 2.99 (dd,J=10.1, 6.2 Hz, 2H), 2.45-2.32 (m, 1H), 2.19-2.06 (m, 1H); ¹³C NMR (101MHz, cdcl₃) δ 177.4, 167.3, 153.8, 144.8, 144.8, 143.0, 131.9, 130.5,129.7, 129.4, 129.1, 128.8, 128.7, 128.6, ff125.6, 125.5, 125.5, 125.5,125.4, 125.4, 125.0, 77.2, 74.8, 63.3, 46.9, 37.4, 34.6, 32.0, 28.0.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(4-(tert-butyl)phenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6h)

¹H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J=1.7 Hz, 1H), 8.13 (dd,J=8.0, 1.8 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.36-7.30 (m, 2H), 7.17-7.13(m, 2H), 5.64 (dd, J=7.8, 4.9 Hz, 1H), 3.98-3.87 (m, 2H), 3.86-3.76 (m,1H), 3.16-3.05 (m, 2H), 2.94-2.83 (m, 2H), 2.50-2.45 (m, 2H), 2.25-2.20(m, 2H), 2.12-1.99 (m, 2H), 1.44 (s, 18H), 1.31 (s, 9H); ¹³C NMR (101MHz, cdcl₃) δ 179.90, 166.72, 161.96, 135.57, 131.46, 131.12, 131.12,130.80, 130.80, 130.62, 130.61, 129.36, 126.90, 126.84, 126.78, 126.34,123.89, 123.06, 121.17, 77.32, 77.20, 77.00, 76.68, 55.31, 49.49, 31.22,29.68, 28.06, 27.97, 27.49, 27.49; Calcd for C₃₆H₄₆F₃N₅O₅Na [M+Na]⁺:709.3418, Found: 709.3374.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(4-hydroxybutoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(19)

¹H NMR (400 MHz, Chloroform-d) δ 10.07 (s, 1H), 8.26 (s, 1H), 8.16 (d,J=2.1 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 5.61-5.52 (m, 1H), 4.15 (d, J=6.1Hz, 2H), 3.91-3.71 (m, 4H), 2.51-2.38 (m, 1H), 2.31-2.11 (m, 2H),2.03-1.91 (m, 2H), 1.81-1.71 (m, 2H), 1.43 (s, 18H); Calcd forC₂₃H₃₃F₃N₅O₅ [M*+]⁻: 514.2272, Found: 514.2259.

Example 41:(S)-2-(3-(4-(2-cyclopropylethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7a, compound 38A)

¹H NMR (500 MHz, Methanol-d₄) δ 8.21 (d, J=1.8 Hz, 1H), 8.18-8.13 (m,1H), 7.59-7.53 (m, 1H), 5.41 (dd, J=8.0, 1.8 Hz, 1H), 3.77-3.68 (m, 1H),3.56 (td, J=9.7, 7.2 Hz, 1H), 2.95-2.86 (m, 0.5H), 2.82-2.74 (m, 1.5H),2.59-2.36 (m, 2H), 2.56-2.38 (m, 1H), 2.21-2.08 (m, 1H), 2.07-1.95 (m,1H), 1.65-1.55 (m, 1.5H), 1.52-1.45 (m, 0.5H), 1.39-1.27 (m, 3H),0.91-0.81 (m, 2H), 0.43-0.38 (m, 0.5H), 0.02-0.01 (m, 0.5H); ¹³C NMR(101 MHz, cd₃od) δ 178.0, 167.2, 155.7, 145.4, 145.1, 132.3, 132.1,130.3, 130.2, 124.3, 124.3, 124.3, 55.1, 36.5, 32.4, 32.3, 32.3, 31.5,31.3, 31.0, 22.9, 22.0, 12.8, 10.3, 3.6; Calcd for C₂₁H₂₇F₃N₅O [M+H]⁺:422.2162, Found: 422.2163.

Example 42:(S)-2-(3-(4-(2-cyclopentylethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7b, compound 44A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.26 (d, J=1.6 Hz, 1H), 8.19 (dd, J=8.0,1.7 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.39 (s, 1H), 5.49-5.39 (m, 1H),3.83-3.72 (m, 1H), 3.70-3.57 (m, 2H), 2.91-2.80 (m, 2H), 2.63-2.43 (m,3H), 2.21 (s, 2H), 2.08 (s, 2H), 1.95-1.76 (m, 4H), 1.71-1.49 (m, 6H),1.37-1.11 (m, 4H); ¹³C NMR (101 MHz, cd₃od) δ 178.0, 167.2, 147.1,134.3, 132.1, 124.3, 95.6, 48.2, 48.0, 47.8, 47.6, 47.4, 47.1, 46.9,40.2, 32.1, 31.7, 31.3, 24.7, 22.9, 19.4, 13.0, 7.8; Calcd forC₂₁H₂₆F₃N₅O [M+H]⁺: 422.2162, Found: 422.

Example 43:(2S,3S)-2-(3-(4-(2-cyclopentylethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidine-1-carboximidamidehydrochloride (7bA, compound 43A)

¹H NMR (500 MHz, Methanol-d₄) δ 8.29 (d, J=1.7 Hz, 1H), 8.23 (dd, J=8.1,1.7 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 5.26 (s, 1H), 3.89-3.81 (m, 2H),3.23 (q, J=7.3 Hz, 2H), 2.92-2.85 (m, 2H), 2.30-2.15 (m, 2H), 1.99-1.82(m, 3H), 1.74-1.53 (m, 4H), 1.33 (t, J=7.3 Hz, 1H), 1.28-1.15 (m, 1H),1.20 (s, 1H); ¹³C NMR (126 MHz, MeOD) δ 175.8, 167.4, 145.7, 132.2,130.3, 128.7, 128.5, 125.3, 124.4, 124.4, 124.3, 124.3, 124.2, 123.2,74.6, 63.4, 56.1, 46.6, 46.0, 40.2, 38.1, 32.2, 31.1, 24.7, 7.8; Calcdfor C₂₁H₂₇F₃N₅O₂ [M+H]⁺: 438.2117, Found: 438.0.

Example 44:(S)-amino(2-(3-(4-(2-cyclohexylethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (7c, compound 76A)

¹H NMR (400 MHz, Methanol-d₄) δ 9.26 (s, 2H), 6.44 (s, 1H), 4.77 (s,1H), 4.70-4.56 (m, 1H), 4.20 (d, J=8.3 Hz, 3H), 3.84 (s, 1H), 3.52 (d,J=26.7 Hz, 2H), 3.15 (d, J=54.8 Hz, 3H), 2.51-2.71 (m, 6H), 2.29 (s,6H), 2.11-1.72 (m, 3H); ¹³C NMR (101 MHz, cd₃od) δ 176.8, 164.8, 156.6,153.2, 129.6, 128.0, 123.2, 122.2, 120.7, 115.7, 110.0, 49.2, 49.0,48.7, 48.5, 48.3, 48.1, 47.9, 34.7, 32.3, 26.9, 22.8, 18.4, 9.5; Calcdfor C₂₂H₂₆F₃N₅O [M+H]⁺: 436.2324, Found: 436.2357.

Example 45:(S)-2-(3-(4-(4-ethylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7i, compound 50A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.30 (d, J=1.7 Hz, 1H), 8.20-8.14 (m,1H), 7.56 (d, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.11 (s, 4H), 5.47 (dd,J=7.9, 1.8 Hz, 1H), 3.83-3.74 (m, 1H), 3.62-3.57 (m, 1H), 3.15-3.07 (m,2H), 2.93-2.85 (m, 2H), 2.64-2.52 (m, 3H), 2.51-2.44 (m, 1H), 2.29-2.17(m, 1H), 2.15-2.01 (m, 1H), 1.20 (t, J=7.6 Hz, 3H); ¹³C NMR (101 MHz,cd₃od) δ 178.1, 167.2, 155.7, 144.2, 142.0, 137.9, 132.4, 130.2, 128.9,128.6, 128.0, 127.5, 125.6, 124.5, 124.4, 124.4, 124.3, 124.3, 124.3,122.9, 55.1, 48.2, 48.1, 48.0, 47.9, 47.8, 47.7, 47.6, 47.6, 47.6, 47.4,47.4, 47.2, 47.2, 46.9, 36.9, 34.8, 34.8, 31.3, 28.1, 22.9, 14.9; Calcdfor C₂₄H₂₆F₃N₅O [M+H]⁺: 458.2168, Found: 458.

Example 46:(S)-2-(3-(4-(4-propylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7d, compound 35A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.30 (d, J=1.8 Hz, 1H), 8.19-8.14 (m,1H), 7.55 (d, J=8.1 Hz, 1H), 7.09 (s, 4H), 5.47 (dd, J=7.9, 1.9 Hz, 1H),3.82-3.74 (m, 1H), 3.69-3.59 (m, 1H), 3.18-3.07 (m, 2H), 2.94-2.86 (m,2H), 2.63-2.44 (m, 4H), 2.29-2.19 (m, 1H), 2.15-2.05 (m, 1H), 1.68-1.54(m, 2H), 0.92 (t, J=7.3 Hz, 3H); ¹³C NMR (126 MHz, MeOD) δ 178.1, 167.2,155.7, 144.2, 140.4, 138.0, 132.5, 130.2, 128.2, 127.9, 124.6, 124.4,124.4, 55.1, 48.1, 48.1, 48.0, 47.9, 47.9, 47.8, 47.7, 47.6, 47.6, 47.5,47.4, 47.4, 47.3, 47.2, 47.1, 37.2, 36.9, 34.8, 31.3, 24.4, 22.9, 12.6;Calcd for C₂₅H₂₉F₃N₅O [M+H]⁺: 4472.2324, Found: 472.

Example 47:(2S,3S)-3-hydroxy-2-(3-(4-(4-propylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7dA, compound 34A)

¹H NMR (500 MHz, Methanol-d₄) δ 8.24-8.17 (m, 1H), 8.07 (td, J=6.1, 5.7,2.9 Hz, 1H), 7.46 (dd, J=8.1, 3.8 Hz, 1H), 5.46 (d, J=4.4 Hz, 0.4H),5.15 (s, 0.4H), 4.71-4.69 (m, 1H), 3.80-3.68 (m, 1H), 3.64-3.54 (m, 1H),3.11-2.95 (m, 2H), 2.85-2.78 (m, 2H), 2.50-2.39 (m, 2H), 2.19-2.03 (m,2H), 1.58-1.41 (m, 8H), 1.28-1.07 (m, 4H), 0.83 (t, J=7.3 Hz, 3H); ¹³CNMR (101 MHz, cd₃od) δ 187.5, 175.8, 167.3, 156.2, 147.2, 144.3, 140.3,137.9, 132.5, 130.2, 129.0, 128.7, 128.2, 127.9, 125.6, 124.5, 122.9,74.6, 63.4, 46.0, 37.2, 34.7, 31.1, 24.3, 12.6; Calcd for C₂₅H₂₉F₃N₅O₂[M+H]⁺: 488.2269, Found: 488.2268.

Example 48:(S)-2-(3-(4-(4-butylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7g, compound 36A)

¹H NMR (500 MHz, Methanol-d₄) δ 8.20 (s, 1H), 8.08 (d, J=7.4 Hz, 1H),7.46 (d, J=7.7 Hz, 1H), 5.39 (s, 1H), 3.45-3.55 (m, 2H), 3.08-2.98 (m,2H), 2.80 (dd, J=9.7, 6.4 Hz, 2H), 2.48 (t, J=7.7 Hz, 3H), 2.14 (s, 1H),1.99 (s, 1H), 1.31-1.17 (m, 4H), 0.84 (t, J=7.3 Hz, 4H). ¹³C NMR (101MHz, cd₃od) δ 178.1, 167.2, 155.7, 154.7, 154.1, 154.0, 151.7, 151.2,144.2, 140.5, 137.9, 132.5, 130.2, 128.1, 128.1, 128.0, 124.6, 85.9,84.5, 55.2, 48.2, 48.0, 47.8, 47.6, 47.4, 47.2, 47.0, 36.9, 34.8, 31.4,26.8, 26.7, 26.7, 23.0, 21.9, 12.9; Calcd for C₂₆H₃₁F₃N₅O [M+H]⁺:486.2481, Found: 486.0.

Example 49:(2S,3S)-2-(3-(4-(4-butylphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidine-1-carboximidamidehydrochloride (7gA, compound 37A)

¹H NMR (500 MHz, Methanol-d₄) δ 8.20 (s, 1H), 8.08 (d, J=7.2 Hz, 1H),7.44-7.35 (m, 1H), 7.00 (s, 4H), 5.15 (s, 1H), 4.73-4.68 (m, 1H),3.83-3.67 (m, 2H), 3.01-2.97 (m, 2H), 2.85-2.75 (m, 2H), 2.51-2.46 (m,2H), 2.21-2.01 (m, 2H), 1.55-1.38 (m, 4H), 1.31-1.15 (m, 6H), 0.84 (t,J=7.3 Hz, 4H); ¹³C NMR (101 MHz, cd₃od) δ 187.6, 175.8, 167.3, 156.2,147.5, 144.3, 140.5, 137.8, 132.5, 130.2, 129.7, 129.4, 129.0, 128.1,127.9, 125.6, 124.4, 124.4, 122.9, 74.6, 63.4, 36.9, 34.8, 33.6, 31.1,21.9, 12.8; Calcd for C₂₆H₃₀F₃N₅O₂ [M+H]⁺: 502.2430, Found: 502.

Example 50:(2S,3S)-3-hydroxy-2-(3-(4-(4-methoxyphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7eA, compound 41A)

¹H NMR (400 MHz, Chloroform-d) δ 10.10 (s, 1H), 8.35 (d, J=1.7 Hz, 1H),8.13 (dd, J=8.0, 1.8 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.18-7.06 (m, 2H),6.90-6.80 (m, 2H), 5.62 (dd, J=7.8, 4.5 Hz, 1H), 3.80 (d, J=0.5 Hz, 5H),3.10 (dd, J=9.9, 6.5 Hz, 2H), 2.94-2.80 (m, 2H), 2.45 (dt, J=13.2, 7.7Hz, 1H), 2.21 (q, J=6.6 Hz, 2H), 2.12-1.94 (m, 1H), 1.74-1.30 (m, 17H);¹³C NMR (101 MHz, cd₃od) δ 175.8, 167.3, 158.3, 156.2, 144.3, 132.7,132.5, 130.2, 129.0, 124.4, 113.5, 74.6, 63.4, 54.2, 48.2, 48.1, 48.0,47.8, 47.6, 47.5, 47.4, 47.3, 47.2, 47.0, 46.9, 46.0, 36.4, 34.9, 34.9,31.1, 26.7; Calcd for C₂₃H₂₅F₃N₅O₃ [M+H]⁺: 476.1909, Found: 476.0.

Example 51:(S)-2-(3-(4-(4-methoxyphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7e, compound 42A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.22 (d, J=1.6 Hz, 1H), 8.13-8.07 (m,1H), 7.47 (d, J=8.0 Hz, 1H), 7.07-7.01 (m, 2H), 6.80-6.72 (m, 2H), 5.44(d, J=7.5 Hz, 1H), 3.73-3.67 (m, 1H), 3.63-3.51 (m, 1H), 3.07-2.97 (m,2H), 2.83-2.74 (m, 2H), 2.58-2.39 (m, 2H), 2.24-2.12 (m, 1H), 2.02 (d,J=8.1 Hz, 1H); ¹³C NMR (101 MHz, cd₃od) δ 178.0, 167.2, 158.2, 155.7,144.1, 144.1, 132.7, 132.4, 130.2, 129.0, 128.9, 128.6, 125.6, 124.5,124.4, 124.4, 124.3, 124.2, 122.9, 113.5, 55.1, 54.3, 54.3, 48.3, 48.1,47.8, 47.7, 47.6, 47.4, 47.2, 47.0, 36.4, 34.9, 34.8, 31.3, 22.9; Calcdfor C₂₃H₂₅F₃N₅O₂ [M+H]⁺: 460.1960, Found: 460.0.

Example 52:(S)-2-(3-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7f, compound 39A)

¹H NMR (500 MHz, Methanol-d₄) δ 8.34 (d, J=1.8 Hz, 1H), 8.23 (dd, J=8.0,1.8 Hz, 1H), 7.62 (dd, J=12.2, 8.0 Hz, 3H), 7.43 (d, J=7.9 Hz, 2H), 5.51(dd, J=8.0, 1.8 Hz, 1H), 3.85-3.77 (m, 1H), 3.65 (td, J=9.7, 7.3 Hz,1H), 3.20 (dd, J=9.8, 6.4 Hz, 2H), 3.10-3.02 (m, 2H), 2.66-2.46 (m, 2H),2.31-2.21 (m, 1H), 2.15-2.05 (m, 1H); ¹³C NMR (101 MHz, cd₃od) δ 178.1,143.5, 132.4, 130.3, 128.8, 128.7, 128.4, 128.1, 125.0, 125.0, 124.9,124.8, 124.5, 124.4, 124.3, 122.9, 55.1, 36.8, 34.1, 31.3, 22.9.

Example 54:(2S,3S)-3-hydroxy-2-(3-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7fA, compound 40A)

¹H NMR (500 MHz, Methanol-d₄) δ 8.22 (dd, J=6.1, 1.6 Hz, 1H), 8.14-8.06(m, 1H), 7.56-7.42 (m, 3H), 7.32-7.28 (m, 2H), 5.45 (d, J=4.4 Hz, 1H),4.10 (d, J=10.2 Hz, 1H), 4.00 (q, J=7.1 Hz, 2H), 3.50 (s, 1H), 3.13-3.05(m, 2H), 2.95 (t, J=7.9 Hz, 2H), 2.12 (d, J=6.0 Hz, 1H), 1.91 (s, 1H);HRMS (ESI+): Calcd for C₂₃H₂₆F₆N₆O₂NH₄ [M+NH₄]⁺: 532.2016, Found:532.1976.

Example 55:(S)-2-(3-(4-(4-(tert-butyl)phenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (7h, compound 62A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.30 (d, J=1.8 Hz, 1H), 8.27-8.15 (m,1H), 7.59 (t, J=8.6 Hz, 1H), 7.37-7.26 (m, 2H), 7.18-7.07 (m, 2H), 5.46(dd, J=7.9, 1.9 Hz, 1H), 3.84-3.73 (m, 1H), 3.68-3.50 (m, 1H), 3.17-3.03(m, 2H), 2.94-2.82 (m, 2H), 2.65-2.42 (m, 2H), 2.33-2.18 (m, 1H),2.17-2.00 (m, 1H), 1.30 (s, 9H); ¹³C NMR (101 MHz, cd₃od) δ 178.1,167.2, 155.7, 148.8, 144.3, 137.7, 132.4, 130.2, 127.7, 125.0, 124.6,124.5, 124.4, 124.4, 124.3, 55.1, 48.2, 48.0, 47.9, 47.8, 47.8, 47.6,47.6, 47.5, 47.4, 47.1, 47.1, 46.9, 46.7, 36.8, 36.8, 34.8, 34.7, 33.8,31.3, 31.3, 30.4, 30.4, 22.9; Calcd for C₂₆H₃₀F₃N₅O [M+H]⁺: 486.2481,Found: 486.0.

tert-butyl(S)-2-(3-(4-(4-hydroxybutoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(23)

¹H NMR (500 MHz, Chloroform-d) δ 8.29 (d, J=2.8 Hz, 1H), 8.20 (d, J=8.2Hz, 1H), 7.13-7.05 (m, 1H), 5.21-5.18 (m, 0.4H), 5.09-5.03 (m, 0.6H),4.21-4.11 (m, 2H), 3.80-3.63 (m, 3H), 3.62-3.45 (m, 1H), 2.51-2.31 (m,1H), 2.21-2.08 (m, 2H), 2.05-1.91 (m, 3H), 1.90-1.71 (m, 3H), 1.52-1.41(m, 3H), 1.31-1.21 (m, 6H).

Example 56:(S)-2-(3-(4-(4-hydroxybutoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (20b, compound 45A)

¹H NMR (500 MHz, Methanol-d₄) δ 8.21-8.11 (m, 2H), 7.34-7.24 (m, 1H),5.41-5.31 (m, 1H), 4.19-4.10 (m, 2H), 3.68-3.41 (m, 7H), 2.55-2.35 (m,2H), 2.21-2.05 (m, 1H), 2.04-1.87 (m, 1H), 1.86-1.74 (m, 2H), 1.73-1.59(m, 2H); ¹³C NMR (126 MHz,) δ 177.8, 167.2, 159.4, 155.7, 132.6, 125.7,118.0, 113.5, 72.2, 71.0, 68.8, 66.7, 61.1, 55.1, 47.9, 47.8, 47.6,47.4, 47.3, 47.3, 47.2, 31.3, 28.6, 25.3, 22.9; Calcd for C₁₈H₂₃F₃N₅O₃[M+H]⁺: 414.1748, Found: 414.175.

tert-butyl(S)-2-(3-(4-(tert-butoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(15)

¹H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J=2.2 Hz, 1H), 8.12 (dd,J=8.7, 2.2 Hz, 1H), 7.32-7.22 (m, 2H), 5.19 (d, J=8.1 Hz, 0H), 5.06 (dd,J=8.4, 3.5 Hz, 1H), 3.70 (d, J=6.8 Hz, 1H), 3.62-3.42 (m, 1H), 2.48-2.28(m, 1H), 2.22-1.94 (m, 4H), 1.51 (d, J=8.2 Hz, 9H), 1.46 (s, 3H), 1.30(s, 5H).

Tert-butyl(S)-2-(3-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(16)

¹H NMR (400 MHz, Methanol-d₄) δ 8.14 (s, 1H), 8.09-7.99 (m, 1H),7.09-6.99 (m, 1H), 5.15-5.01 (m, 1H), 3.69-3.59 (m, 1H), 3.51-3.41 (m,1H), 2.53-2.34 (m, 1H), 2.19-1.92 (m, 3H), 1.44 (s, 3H), 1.25 (s, 6H);¹³C NMR (101 MHz, cd₃od) δ 181.0, 180.6, 167.2, 158.6, 154.7, 154.0,131.9, 125.7, 124.9, 122.2, 117.1, 80.5, 53.8, 46.5, 46.1, 31.8, 31.0,27.0, 23.9, 23.3.

Tert-butyl(S)-2-(3-(4-(4-hydroxybutoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(23)

¹H NMR (400 MHz, Chloroform-d) 68.28-8.24 (m, 1H), 8.20-8.16 (m, 1H),7.10-7.01 (m, 1H), 5.23-4.92 (m, 1H), 4.16 (t, J=6.0 Hz, 1H), 3.72 (q,J=6.3 Hz, 3H), 3.64-3.39 (m, 1H), 2.41-2.25 (m, 1H), 2.20-2.06 (m, 2H),2.05-1.88 (m, 3H), 1.81-1.61 (m, 4H), 1.45 (s, 3H), 1.29 (s, 5H); ¹³CNMR (101 MHz, cdcl₃) δ 180.8, 180.4, 167.2, 159.0, 153.2, 132.4, 126.5,118.5, 112.9, 80.5, 68.8, 62.0, 53.7, 46.6, 46.3, 32.3, 31.4, 28.9,28.3, 28.1, 25.4, 24.3, 23.6.

(S)-(2-(3-(4-(4-acetoxybutoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(amino)methaniminium2,2,2-trifluoroacetate (20a)

¹H NMR (400 MHz, Methanol-di) δ 8.28-8.21 (m, 2H), 7.34 (d, J=8.7 Hz,1H), 5.44 (dd, J=7.9, 1.9 Hz, 1H), 4.22 (t, J=5.8 Hz, 2H), 4.15 (t,J=6.2 Hz, 2H), 3.77 (td, J=9.3, 2.6 Hz, 1H), 3.61 (td, J=9.7, 7.2 Hz,1H), 2.64-2.43 (m, 2H), 2.22 (s, 1H), 2.02 (s, 4H), 1.98-1.80 (m, 4H);¹³C NMR (101 MHz, cdcl₃) δ 184.5, 171.7, 161.7, 143.0, 141.2, 138.2,137.6, 132.5, 111.6, 98.2, 77.3, 68.2, 63.9, 59.2, 54.4, 49.5, 49.5,49.3, 49.1, 48.9, 48.6, 48.4, 48.2, 45.1, 40.6, 25.4, 24.9, 20.7; Calcdfor C₂₃H₃₀F₃N₃O₅Na [M+H]⁺: 456.1853, Found: 455.

Tert-butyl(S)-2-(3-(4-(4-methoxybutoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(24)

¹H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 8.17 (d, J=8.6 Hz, 1H),7.10-6.99 (m, 1H), 5.19-5.14 (m, 0.4H), 5.07-5.01 (m, 0.6H), 4.13 (t,J=6.1 Hz, 2H), 3.79-3.61 (m, 1H), 3.59-4.41 (m, 5H), 2.51-2.29 (m, 1H),2.18-2.05 (m, 2H), 2.04-1.82 (m, 3H), 1.79-1.71 (m, 2H), 1.44 (s, 3H),1.28 (s, 6H); ¹¹C NMR (101 MHz, cdcl₃) δ 167.2, 132.4, 112.9, 80.5,72.1, 68.8, 58.5, 53.8, 53.4, 46.3, 32.4, 28.3, 28.1, 25.9, 25.8, 23.7;Calcd for C₂₃H₃₀F₃N₃O₅Na [M+Na]⁺: 509.2061, Found: 509.2039.

Tert-butyl(S)-2-(4-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)oxazol-2-yl)pyrrolidine-1-carboxylate(21)

¹H NMR (500 MHz, Chloroform-d) δ 8.33 (d, J=2.2 Hz, 1H), 8.21 (dd,J=8.3, 2.5 Hz, 1H), 7.41-7.35 (m, 4H), 7.34-7.30 (m, 1H), 7.16-7.08 (m,1H), 5.25-5.15 (m, 0.4H), 5.11-5.05 (m, 0.6H), 4.68 (s, 2H), 4.35-4.29(m, 2H), 3.95-3.89 (m, 2H), 3.79-3.65 (m, 1H), 3.63-3.46 (m, 1H),2.48-2.32 (m, 1H), 2.25-2.15 (m, 2H), 2.09-1.99 (m, 1H), 1.48 (s, 3H),1.32 (s, 6H); ¹³C NMR (101 MHz, cdcl₃) δ 180.5, 167.4, 153.8, 153.8,137.7, 132.0, 128.4, 128.4, 127.8, 127.8, 127.8, 117.3, 110.0, 80.8,73.2, 71.5, 69.9, 61.4, 53.8, 49.5, 49.3, 49.0, 48.8, 48.6, 46.3, 32.2,28.2, 28.0, 24.2, 23.6, 21.8; Calcd for C₂₇H₃₀F₃N₃O₅Na [M+Na]⁺: 556.2061Found: 556.2082.

tert-butyl(S,E)-((2-(3-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J=1.8 Hz, 1H), 8.13 (dd,J=8.0, 1.8 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.35-7.30 (m, 2H), 7.17-7.13(m, 2H), 5.64 (dd, J=7.8, 4.9 Hz, 1H), 3.97-3.87 (m, 1H), 3.87-3.76 (m,1H), 3.15-3.07 (m, 2H), 2.92-2.83 (m, 2H), 2.53-2.39 (m, 1H), 2.31-2.15(m, 2H), 2.11-1.97 (m, 1H), 1.44 (s, 18H), 1.31 (s, 9H); ¹³C NMR (101MHz, cdcl₃) δ 179.2, 167.4, 153.6, 149.1, 143.9, 137.9, 132.0, 131.9,130.4, 129.3, 129.0, 128.9, 128.7, 128.1, 127.6, 125.6, 125.5, 125.4,125.3, 125.2, 125.20, 124.8, 122.8, 81.3, 55.4, 49.7, 37.3, 35.0, 34.4,31.4, 31.2, 29.7, 28.0, 27.9, 27.6, 24.1;

tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(4-methoxybutoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(25)

¹H NMR (400 MHz, Chloroform-d) δ 8.29-8.26 (m, 1H), 8.21-8.14 (m, 1H),7.11-6.95 (m, 1H), 5.65-5.55 (m, 1H), 4.21-4.10 (m, 3H), 3.95-3.75 (m,2H), 3.46 (t, 2H), 3.31 (s, 2H), 2.51-2.38 (m, 1H), 2.25-2.10 (m, 2H),2.09-1.91 (m, 1H), 1.90-1.87 (m, 2H), 1.82-1.72 (m, 2H), 1.48-1.35 (m,13H), 1.32-1.15 (m, 9H).

Example 57:(S)-2-(3-(4-(4-methoxybutoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide2,2,2-trifluoroacetate (26, compound 46A)

¹H NMR (500 MHz, Methanol-d₄) δ 8.24-7.85 (m, 1H), 7.26-7.21 (m, 1H),5.35 (dd, J=8.0, 1.9 Hz, 1H), 4.11 (t, J=6.1 Hz, 1H), 3.24 (s, 2H),3.22-3.20 (m, 3H), 2.51-2.31 (m, 2H), 2.21-2.11 (m, 1H), 2.05-1.91 (m,1H), 1.81-1.75 (m, 2H), 1.71-1.62 (m, 2H), 1.51-1.32 (m, 1H), 1.18 (s,3H);

Example 58:(S)-2-(4-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)oxazol-2-yl)pyrrolidine-1-carboximidamidehydrochloride (22, compound 63A)

was synthesized using general procedure and isolated as a white solid(12 mg, 80%). ¹H NMR (400 MHz, Methanol-d₄) δ 8.26-8.21 (m, 2H),7.44-7.21 (m, 6H), 5.48-5.40 (dd, J=7.6, 1.8 Hz, 1H), 4.63 (s, 2H),4.40-4.33 (m, 2H), 3.93-3.85 (m, 2H), 3.83-3.69 (m, 1H), 3.67-3.56 (m,1H), 2.58-2.41 (m, 2H), 2.25-2.03 (m, 2H); ¹³C NMR (101 MHz,Methanol-d₄) δ 177.81, 167.09, 159.26, 155.65, 138.10, 132.48, 127.93,127.27, 125.68, 125.63, 121.91, 119.16, 118.85, 118.31, 113.80, 72.84,68.80, 68.02, 55.06, 48.21, 48.00, 48.00, 47.79, 47.57, 47.36, 47.33,47.15, 46.94, 31.32, 22.91; Calcd for C₂₃H₂₅F₃N₅O₃ [M+H]⁺: 478.1961,Found: 478.1989.

Examples 59-83 Synthesis and Characterization of Formulae IA and IBCompounds

Schemes 12 and 13 below outline general and specific syntheticmethodologies for the preparation of Compound Nos. 12A, 14A-16A, 52A,53A, 57A-59A, 61A, and 65A-75A. Compound numbering in Schemes 12 and 13are internal to the Schemes, while the subsequent procedures refer whereapplicable to the final compounds.

General Procedures General Procedure 1—Williamson Ether Synthesis

6-Hydroxy-2-napthalnitrile 1 (1 equiv.), potassium carbonate (4 equiv.)and alkyl halide (1.2 equiv.) were added to a round bottom flaskcontaining acetonitrile. The reaction mixture was heated to 80° C. for4-12 hours until TLC indicated the starting material had been fullyconsumed. The reaction mixture was extracted with ethyl acetate and D.I.water. The combined organic layers were washed with brine and dried oversodium sulfate. After filtration and concentration via reduced pressure,the resulting brown oil was purified on a silica column with hexane andethyl acetate.

General Procedure 2—Amidoxime Formation

Nitrile 2a-d (1 equiv.), hydroxylamine hydrochloride (3 equiv.), TEA (3equiv.) were added to a round bottom flask containing ethanol. Thereaction mixture was heated to 80° C. for 6-12 hours and monitored viaTLC. Once the starting material was consumed, the solution was cooled toroom temperature, concentrated under reduced pressure, loaded ontocelite, and purified on a silica column with hexane and ethyl acetate.

General Procedure 3-1,2,4-Oxadiazole Formation with HCTU

Amidoxime (3a-d) (1 equiv.), Boc-L-proline (1.4 equiv.) orBoc-trans-3-hydroxy-L-proline (1.4 equiv.), and DIEA (1.4 equiv.) wereadded to a round bottom flask containing DMF. HCTU (1.8 equiv.) wasadded to the reaction solution, the flask was connected to a refluxcondenser and heated to 120° C. for 12-16 hours. Once the reactioncooled to room temperature, the solution was extracted with ethylacetate and saturated LiBr solution. The combined organic layers werewashed with brine and dried over sodium sulfate. After filtration toremove the sodium sulfate and concentration via reduced pressure, theresulting brown oil was purified on a silica column with hexane andethyl acetate.

General Procedure 4—Boc-Deprotection

Boc-amine 4a-e or Di-Boc-guanidine 6a-e was dissolved in methanol. HClgas was bubbled into the solution for 1 minute. The solution was stirreduntil TLC indicated that all of the Boc-protected amine had beenconsumed. The solvent was removed under reduced pressure. The resultingwhite to light yellow solid was washed with diethyl ether to yield pureproduct.

General Procedure 5—Guanylation of Secondary Amines

Hydrogen chloride salt 5a-e (1 equiv.) was added to a round bottom flaskwith acetonitrile and DIEA (3 equiv.). The solution was allowed to stirfor 10 minutes before the addition of (Z)-Tert-butyl(((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (1.05equiv.). The solution was stirred at room temperature under nitrogenuntil TLC indicated that the starting material had been consumed.

General Procedure 6—Amidoxime Formation in Microwave

Nitrile 1 (1 equiv.), hydroxylamine hydrochloride (2 equiv.), TEA (3equiv.) were added to a 20 mL microwave vial containing ethanol. Thereaction mixture was heated to 150° C. for 2 minutes in the microwave.The reaction mixture was concentrated under reduced pressure, loadedonto celite, and purified on a silica column with 80-100% ethyl acetateand hexane.

General Procedure 7-1,2,4-Oxadiazole Formation with PyBOP

Amidoxime (8) (1 equiv.), Boc-L-proline (1.1 equiv.), and DIEA (3equiv.) were added to a round bottom flask containing DMF. PyBOP (1.2equiv.) was added to the flask and the solution was heated to 110° C.overnight. Once the reaction cooled to room temperature, the solutionwas extracted with ethyl acetate and saturated Na₂CO₃ solution. Thecombined organic layers were washed with brine and dried over sodiumsulfate. After filtration to remove the sodium sulfate and concentrationvia reduced pressure, the resulting brown oil was purified on a silicacolumn with 20-35% ethyl acetate in hexane.

General Procedure 8—Boc-Deprotection in Microwave

Boc-amine 9 or Di-Boc-guanidine 11, 6k-bb was dissolved in a 4N HCl indioxane solution (3 equiv.). The solution was heated to 100° C. for 1minute in the microwave. The solvent was removed under reduced pressure.The resulting white to light yellow solid was washed with diethyl etherto yield pure product.

General Procedure 9—Guanylation of Secondary Amines in Microwave

Hydrogen chloride salt 10 (1 equiv.) was added to microwave vial withacetonitrile and DIEA (3 equiv.). The solution was allowed to stir for30 seconds before the addition of (Z)-Tert-butyl(((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (0.8equiv.) The solution was heated to 85° C. in the microwave for 30minutes. The solvent was removed by reduced pressure and the resultingresidue was purified on a silica column with hexane and ethyl acetate.

General Procedure 10—Williamson Ether Synthesis in Microwave

Di-Boc-guanidine 11 (1 equiv.), potassium carbonate (2 equiv.) alkylhalide (1.2 equiv.), and sodium iodide (0.1 equiv.) were added to amicrowave vial containing ethanol. The reaction mixture was heated to100° C. for 15. The solvent was removed under reduced pressure and theresulting residue was extracted with ethyl acetate and D.I. water. Thecombined organic layers were washed with brine and dried over sodiumsulfate. After filtration and concentration via reduced pressure, theresulting residue was purified on a silica column with hexane and ethylacetate.

Synthesis and Characterization 6-(butyloxy)-2-naphthonitrile (2a)

2a was synthesized using general procedure 1. Purification on a silicagel column with 0-20% ethyl acetate in hexanes produced 2a (498 mg,93%), a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.05 (d, J=1.7 Hz, 1H),7.71 (dd, J=8.7, 2.6 Hz, 2H), 7.50 (dd, J=8.5, 1.7 Hz, 1H), 7.21 (dd,J=9.0, 2.5 Hz, 1H), 7.09 (d, J=2.5 Hz, 1H), 4.06 (t, J=6.5 Hz, 2H),1.87-1.78 (m, 2H), 1.53 (h, J=7.5 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). ¹³CNMR (126 MHz, CDCl₃) δ 159.55, 136.43, 133.66, 129.84, 127.72, 127.55,126.90, 120.92, 119.64, 106.51, 106.45, 67.97, 31.13, 19.28, 13.87. HRMS(ESI+): Calcd for C₁₅H₁₅N₀ [M+H]⁺: 226.2936, Found: 226.1230.

6-(pentyloxy)-2-naphthonitrile (2b)

2b was synthesized using general procedure 1. Purification on a silicagel column with 0-20% ethyl acetate in hexanes produced 2b (416 mg,98%), a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.75 (dd,J=8.7, 3.3 Hz, 2H), 7.53 (dd, J=8.5, 1.6 Hz, 1H), 7.26-7.22 (m, 1H),7.12 (d, J=2.3 Hz, 1H), 4.09 (t, J=6.6 Hz, 2H), 1.90-1.82 (m, 2H),1.54-1.37 (m, 4H), 0.96 (t, J=7.2 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ159.69, 136.58, 133.83, 129.99, 127.84, 127.73, 127.08, 121.05, 119.74,106.69, 106.66, 77.48, 77.16, 76.84, 68.42, 28.91, 28.32, 22.56, 14.13.HRMS (ESI+): Calcd for C₁₆H₁₇NO [M+H]⁺: 240.3032, Found: 240.1381.

6-(hexyloxy)-2-naphthonitrile (2c)

2c was synthesized using general procedure 1. Purification on a silicagel column with 0-20% ethyl acetate in hexanes produced 2c (517 mg,86%), a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.06 (d, J=1.6 Hz, 1H),7.72 (d, J=8.7 Hz, 2H), 7.51 (dd, J=8.4, 1.7 Hz, 1H), 7.22 (dd, J=9.0,2.5 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 4.06 (t, J=6.6 Hz, 2H), 1.84 (p,J=6.7 Hz, 2H), 1.50 (p, J=7.1 Hz, 2H), 1.41-1.31 (m, 4H), 0.99-0.88 (m,3H). ¹³C NMR (126 MHz, CDCl₃) δ 159.58, 136.46, 133.69, 129.87, 127.74,127.59, 126.93, 120.95, 119.66, 106.54, 106.49, 77.41, 77.16, 76.91,68.31, 31.60, 29.09, 25.77, 22.64, 14.09. HRMS (ESI+): Calcd forC₁₇H₁₉N₀ [M+H]⁻: 254.3468, Found: 254.1536.

6-(heptyloxy)-2-naphthonitrile (2d)

2d was synthesized using general procedure 1. Purification on a silicagel column with 0-20% ethyl acetate in hexanes produced 2d (147 mg,85%), a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.75 (dd,J=8.8, 2.2 Hz, 2H), 7.53 (dd, J=8.5, 1.6 Hz, 1H), 7.29-7.19 (m, 1H),7.12 (d, J=2.4 Hz, 1H), 4.08 (t, J=6.6 Hz, 2H), 1.92-1.80 (m, 2H), 1.50(ddd, J=15.5, 8.9, 6.8 Hz, 2H), 1.36 (m, 6H), 0.96-0.85 (m, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 159.68, 136.57, 133.81, 129.97, 127.82, 127.71,127.06, 121.04, 119.72, 106.68, 106.64, 68.42, 31.88, 29.21, 29.15,26.13, 22.72, 14.19. HRMS (ESI+): Calcd for C₁₈H₂₁N₀ [M+H]⁺: 268.3734,Found: 268.1681.

6-isobutoxy-2-naphthonitrile (2e)

2e was synthesized using general procedure 1. Purification on a silicagel column with 0-20% ethyl acetate in hexanes produced 2e (223 mg,84%), a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.09-8.05 (m, 1H), 7.73(d, J=8.7 Hz, 2H), 7.51 (dd, J=8.5, 1.6 Hz, 1H), 7.27-7.20 (m, 1H), 7.11(d, J=2.4 Hz, 1H), 3.85 (d, J=6.5 Hz, 2H), 2.16 (dt, J=13.3, 6.7 Hz,1H), 1.08 (d, J=6.7 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 159.71, 136.51,133.73, 129.89, 127.76, 127.65, 126.98, 120.99, 119.69, 106.66, 106.56,77.48, 77.16, 76.84, 74.67, 28.28, 19.32. HRMS (ESI+): Calcd forC₁₅H₁₅NO [M+H]⁺: 226.2936, Found: 226.1234.

6-(benzyloxy)-2-naphthonitrile (2f)

2f was synthesized using general procedure 1. Purification on a silicagel column with 0-20% ethyl acetate in hexanes produced 2f (153 mg,100%), a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.75 (dd,J=8.7, 5.3 Hz, 2H), 7.55-7.48 (m, 3H), 7.44 (t, J=7.3 Hz, 2H), 7.42-7.37(m, 1H), 7.33 (dd, J=9.0, 2.4 Hz, 1H), 7.23 (d, J=2.1 Hz, 1H), 5.20 (s,2H). ¹³C NMR (101 MHz, CDCl₃) δ 159.09, 136.31, 136.18, 133.69, 130.05,128.73, 128.30, 127.85, 127.78, 127.58, 127.01, 120.91, 119.57, 107.24,106.80, 70.22. HRMS (ESI+): Calcd for C₁₈H₁₃NO [M+H]⁺: 260.3099, Found:260.1060.

6-((4-methylbenzyl)oxy)-2-naphthonitrile (2g)

2g was synthesized using general procedure 1. Purification on a silicagel column with 0-20% ethyl acetate in hexanes produced 2g (237 mg,98%), a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.74 (dd,J=8.7, 4.9 Hz, 2H), 7.52 (dd, J=8.5, 1.6 Hz, 1H), 7.37 (d, J=8.0 Hz,2H), 7.30 (dd, J=9.0, 2.5 Hz, 1H), 7.23 (dd, J=8.4, 2.3 Hz, 3H), 5.15(s, 2H), 2.38 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 159.24, 138.19,136.39, 133.76, 133.17, 130.06, 129.46, 127.90, 127.82, 127.78, 127.05,121.04, 119.63, 107.26, 106.82, 70.25, 21.28. HRMS (ESI+): Calcd forC₁₉H₁₅NO [M+H]⁻: 274.3364, Found: 274.1237.

6-cyanonaphthalen-2-yl 4-methylbenzenesulfonate (2h)

2h was synthesized using general procedure 1. Purification on a silicagel column with 0-20% ethyl acetate in hexanes produced 2h (242 mg,95%), a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.80 (d,J=8.6 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.53 (s,1H), 7.29 (d, J=7.9 Hz, 2H), 7.20 (d, J=8.6 Hz, 1H), 2.42 (s, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 149.40, 145.91, 134.99, 133.88, 132.20, 130.69,130.52, 130.02, 129.22, 128.51, 127.41, 123.18, 120.20, 118.80, 110.02,21.79. HRMS (ESI+): Calcd for C₁₈H₁₃NO₃S [M+Cl]⁻: 358.8187, Found:358.0309.

N′-hydroxy-6-(butyloxy)-2-naphthimidamide (3a)

3a was synthesized using general procedure 2. Purification on a silicagel column with 50-100% ethyl acetate in hexanes produced 3a as amixture of enantiomers (192 mg, 67%), a white solid. ¹H NMR (400 MHz,CD₃OD) δ 8.04-8.01 (m, 1H), 7.87-7.65 (m, 3H), 7.25-7.10 (m, 2H),4.13-4.04 (m, 2H), 1.86-1.73 (m, 2H), 1.59-1.48 (m, 2H), 0.99 (td,J=7.4, 1.2 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD) δ 171.14, 158.79, 157.92,154.22, 136.69, 135.46, 130.11, 129.44, 128.29, 128.21, 127.86, 127.72,127.62, 126.60, 126.48, 124.99, 124.12, 123.64, 119.49, 119.10, 106.01,105.96, 67.46, 67.38, 31.03, 30.99, 18.93, 18.92, 12.76. HRMS (ESI+):Calcd for C₁₅H₁₈N₂O₂ [M+H]⁺: 259.3236, Found: 259.1417.

N′-hydroxy-6-(pentyloxy)-2-naphthimidamide (3b)

3b was synthesized using general procedure 2. Purification on a silicagel column with 50-100% ethyl acetate in hexanes produced 3b as amixture of enantiomers (360 mg, 99%), a white solid. ¹H NMR (400 MHz,MeOD) δ 8.05 (d, J=1.4 Hz, 1H), 7.81-7.68 (m, 3H), 7.22 (d, J=2.5 Hz,1H), 7.15 (dd, J=8.9, 2.5 Hz, 1H), 4.10 (t, J=6.5 Hz, 2H), 1.85 (dd,J=8.2, 6.6 Hz, 2H), 1.56-1.38 (m, 4H), 0.97 (t, J=7.2 Hz, 3H). ¹³C NMR(101 MHz, MeOD) δ 159.35, 155.65, 136.90, 130.89, 129.74, 129.09,127.92, 126.42, 125.09, 120.55, 107.46, 69.12, 49.64, 49.43, 49.21,49.00, 48.79, 48.57, 48.36, 30.08, 29.46, 23.55, 14.38. HRMS (ESI+):Calcd for C₁₆H₂₀N₂O₂ [M+H]⁺: 273.3501, Found: 273.1610.

6-(hexyloxy)-N′-hydroxy-2-naphthimidamide (3c)

3c was synthesized using general procedure 2. Purification on a silicagel column with 50-100% ethyl acetate in hexanes produced 3c as amixture of enantiomers (225 mg, 77%), a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.35 (d, J=1.6 Hz, 0H), 8.05 (d, J=1.4 Hz, 1H), 7.91-7.65 (m,4H), 7.28-7.10 (m, 2H), 4.10 (dt, J=7.7, 6.5 Hz, 2H), 1.87-1.80 (m, 2H),1.59-1.48 (m, 2H), 1.41-1.36 (m, 4H), 0.97-0.91 (m, 3H). ¹³C NMR (101MHz, MeOD) δ 158.79, 157.91, 136.69, 135.46, 130.12, 129.44, 128.29,128.22, 127.86, 127.72, 127.64, 126.60, 126.47, 124.98, 124.12, 123.64,119.49, 119.10, 106.02, 105.97, 67.77, 67.69, 48.19, 47.98, 47.77,47.55, 47.34, 47.13, 46.91, 31.35, 31.34, 28.90, 28.86, 25.48, 22.24,12.92. HRMS (ESI+): Calcd for C₁₇H₂₂N₂O₂ [M+H]⁺: 287.3767, Found:287.1728.

6-(heptyloxy)-N′-hydroxy-2-naphthimidamide (3d)

3d was synthesized using general procedure 2. Purification on a silicagel column with 50-100% ethyl acetate in hexanes produced 3d as amixture of enantiomers (60 mg, 71%), a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.26 (s, 1H), 7.83-7.73 (m, 3H), 7.20 (dd, J=8.9, 2.5 Hz, 1H),7.14 (d, J=2.4 Hz, 1H), 4.09 (t, J=6.6 Hz, 2H), 1.90-1.82 (m, 2H),1.54-1.46 (m, 2H), 1.43-1.28 (m, 7H), 1.26 (s, 1H), 0.93-0.86 (m, 4H).¹³C NMR (101 MHz, CDCl₃) δ 169.58, 159.01, 136.79, 130.63, 128.14,128.01, 127.29, 124.41, 120.30, 106.54, 68.35, 31.94, 29.33, 29.22,26.21, 22.77, 14.23. HRMS (ESI+): Calcd for C₁₈H₂₄N₂O₂ [M+H]⁺: 301.4033,Found: 301.1920.

N′-hydroxy-6-isobutoxy-2-naphthimidamide (3e)

3e was synthesized using general procedure 2. Purification on a silicagel column with 50-100% ethyl acetate in hexanes produced 3e as amixture of enantiomers (221 mg, 91%), a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.30-8.23 (m, 1H), 7.99 (s, 0H), 7.86-7.67 (m, 3H), 7.20 (ddd,J=12.1, 8.9, 2.5 Hz, 1H), 7.13 (dd, J=8.7, 2.5 Hz, 1H), 3.85 (dd, J=6.5,5.2 Hz, 2H), 2.16 (td, J=6.7, 3.0 Hz, 1H), 1.08 (dd, J=6.7, 1.6 Hz, 6H).¹³C NMR (101 MHz, CDCl₃) δ 169.67, 159.10, 158.29, 153.21, 136.80,135.66, 130.62, 129.97, 128.41, 128.15, 127.32, 127.28, 125.17, 124.41,123.81, 120.32, 119.95, 106.65, 106.56, 74.70, 74.66, 29.85, 28.42,19.47. HRMS (ESI+): Calcd for C₁₅H₁₈N₂O₂[M+H]⁺: 259.3236, Found:259.1465.

6-(benzyloxy)-N′-hydroxy-2-naphthimidamide (3f)

3e was synthesized using general procedure 2. Purification on a silicagel column with 50-100% ethyl acetate in hexanes produced 3f as amixture of enantiomers (122 mg, 90%), a white solid. ¹H NMR (400 MHz,DMSO) δ 8.06 (s, 1H), 7.80-7.75 (m, 1H), 7.74-7.67 (m, 2H), 7.47-7.44(m, 2H), 7.38-7.33 (m, 3H), 7.31-7.26 (m, 1H), 7.19 (dd, J=9.0, 2.5 Hz,1H), 5.79 (s, 2H), 5.17 (d, J=7.8 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ156.75, 150.86, 136.91, 134.47, 129.87, 128.52, 127.98, 127.90, 126.43,124.23, 123.91, 119.15, 107.32, 69.42.

N′-hydroxy-6-((4-methylbenzyl)oxy)-2-naphthimidamide (3g)

3g was synthesized using general procedure 2. Purification on a silicagel column with 50-100% ethyl acetate in hexanes produced 3g as amixture of enantiomers (175 mg, 98%), a white solid. ¹H NMR (400 MHz,CD₃OD) δ 8.06 (d, J=1.7 Hz, 1H), 7.88 (dd, J=8.6, 1.6 Hz, 1H), 7.84-7.79(m, 1H), 7.76-7.69 (m, 1H), 7.41-7.29 (m, 3H), 7.28-7.14 (m, 3H), 5.16(d, J=8.1 Hz, 2H), 2.35 (s, 3H).

6-(N′-hydroxycarbamimidoyl)naphthalen-2-yl 4-methylbenzenesulfonate (3h)

3h was synthesized using general procedure 2. Purification on a silicagel column with 50-100% ethyl acetate in hexanes produced 3h as amixture of enantiomers (122 mg, 92%), a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.06-8.02 (m, 1H), 7.81-7.76 (m, 3H), 7.73 (dd, J=8.4, 1.9 Hz,2H), 7.48 (d, J=2.4 Hz, 1H), 7.33-7.28 (m, 2H), 7.14 (dd, J=8.9, 2.4 Hz,1H), 4.97 (s, 2H), 2.45 (s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 152.48,148.08, 145.65, 134.28, 132.52, 131.57, 130.54, 130.41, 129.97, 128.70,128.55, 125.09, 124.45, 122.13, 120.01, 21.88. HRMS (ESI+): Calcd forC₁₈H₁₆N₂O₄S [M+H]⁺: 357.4036, Found: 357.0922.

Tert-butyl(S)-2-(3-(6-(butyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4a)

4a was synthesized using general procedure 3. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 4a (63 mg,39%), a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=1.9 Hz, 1H),8.08 (d, J=8.5 Hz, 1H), 7.86-7.74 (m, 2H), 7.24-7.11 (m, 2H), 5.28-5.06(m, 1H), 4.10 (t, J=6.4 Hz, 2H), 3.82-3.66 (m, 1H), 3.63-3.47 (m, 1H),2.49-2.34 (m, 1H), 2.29-2.12 (m, 2H), 2.09-1.95 (m, 1H), 1.84 (p, J=6.4Hz, 2H), 1.60-1.50 (m, 2H), 1.50-1.23 (m, 8H), 1.01 (t, J=7.4 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 180.66, 168.68, 158.66, 153.72, 136.32,130.41, 128.49, 127.88, 127.55, 124.46, 121.81, 120.06, 106.75, 80.60,67.97, 54.02, 46.52, 32.58, 31.38, 28.55, 28.31, 23.87, 19.44, 13.99.HRMS (ESI+): Calcd for C₂₅H₃₁N₃O₄ [M+Na]⁺: 460.5211, Found: 460.2208.

Tert-butyl(S)-2-(3-(6-(pentyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4b)

4b was synthesized using general procedure 3. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 4b (65 mg,49%), a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 8.08 (d,J=8.5 Hz, 1H), 7.81 (dd, J=15.8, 8.8 Hz, 2H), 7.22-7.13 (m, 2H),5.26-5.07 (m, 1H), 4.08 (t, J=6.6 Hz, 2H), 3.79-3.66 (m, 1H), 3.62-3.47(m, 1H), 2.47-2.32 (m, 1H), 2.22-2.13 (m, 2H), 2.07-1.97 (m, 1H), 1.86(p, J=6.6 Hz, 2H), 1.76 (s, 0H), 1.54-1.24 (m, 13H), 0.95 (t, J=7.2 Hz,3H). ¹³C NMR (101 MHz, CDCl₃) δ 180.49, 168.50, 158.48, 153.56, 136.15,130.23, 128.32, 127.71, 127.38, 127.24, 124.42, 124.28, 121.62, 119.89,106.57, 80.43, 77.32, 77.01, 76.69, 68.10, 53.85, 46.62, 46.35, 32.40,31.50, 28.85, 28.37, 28.22, 28.13, 24.36, 23.70, 22.43, 13.99. HRMS(ESI+): Calcd for C₂₆H₃₃N₃O₄ [M+H]⁺: 452.5659, Found: 452.2535.

Tert-butyl(S)-2-(3-(6-(hexyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4c)

4c was synthesized using general procedure 3. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 4c (67 mg,37%), a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.58-8.49 (m, 1H), 8.08(dd, J=8.2, 1.8 Hz, 1H), 7.87-7.72 (m, 2H), 7.25-7.10 (m, 2H), 5.17(ddd, J=73.1, 8.3, 3.3 Hz, 1H), 4.09 (t, J=6.6 Hz, 2H), 3.78-3.70 (m,1H), 3.65-3.48 (m, 1H), 2.50-2.33 (m, 1H), 2.21-2.16 (m, 2H), 2.03-2.01(m, 1H), 1.85 (p, J=6.8 Hz, 2H), 1.58-1.16 (m, 17H), 0.96-0.88 (m, 3H).¹³C NMR (126 MHz, CDCl₃) δ 180.65, 168.67, 158.64, 153.72, 136.30,130.41, 128.47, 127.87, 127.55, 127.40, 124.59, 124.44, 121.76, 120.07,119.93, 106.69, 80.60, 68.27, 54.01, 46.51, 32.58, 31.73, 29.29, 28.54,28.30, 25.91, 23.87, 22.76, 14.19. HRMS (ESI+): Calcd for C₂₇H₃₅N₃O₄[M+Na]⁺: 488.5743, Found: 488.2527.

Tert-butyl(S)-2-(3-(6-(heptyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4d)

4d was synthesized using general procedure 3. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 4d (30 mg,63%), a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 8.08 (d,J=8.5 Hz, 1H), 7.81 (dd, J=15.8, 8.8 Hz, 1H), 7.23-7.10 (m, 1H),5.28-5.04 (m, 1H), 4.09 (t, J=6.6 Hz, 1H), 3.78-3.65 (m, 1H), 3.63-3.44(m, 1H), 2.49-2.28 (m, 1H), 2.23-2.14 (m, 2H), 2.07-1.96 (m, 1H), 1.86(dt, J=14.5, 6.6 Hz, 2H), 1.71-1.24 (m, 12H), 0.94-0.84 (m, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 180.67, 168.69, 158.67, 153.75, 136.33, 130.43,128.50, 127.90, 127.56, 124.47, 121.80, 120.08, 106.76, 80.64, 68.31,54.03, 46.54, 32.60, 31.94, 29.35, 29.22, 28.56, 28.32, 26.21, 23.89,22.77, 14.23. HRMS (ESI+): Calcd for C₂₈H₃₇N₃O₄ [M+Na]⁺: 502.6008,Found: 502.2706.

Tert-butyl(S)-2-(3-(6-isobutoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4e)

4e was synthesized using general procedure 3. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 4e (176 mg,87%), a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 8.08 (d,J=8.5 Hz, 1H), 7.81 (dd, J=17.0, 8.8 Hz, 2H), 7.23-7.09 (m, 2H), 5.09(dd, J=8.1, 3.6 Hz, 1H), 3.86 (d, J=6.5 Hz, 2H), 3.80-3.66 (m, 1H), 3.58(d, J=10.5 Hz, 1H), 2.42 (s, 1H), 2.23-2.11 (m, 3H), 2.02 (d, J=4.9 Hz,1H), 1.47 (d, J=6.3 Hz, 3H), 1.31 (s, 6H), 1.08 (d, J=6.7 Hz, 6H). ¹³CNMR (101 MHz, CDCl₃) δ 180.49, 168.51, 158.59, 136.16, 130.22, 128.32,127.72, 127.37, 124.29, 121.62, 119.91, 106.61, 80.44, 74.49, 53.85,46.35, 32.41, 28.38, 28.23, 28.14, 23.70, 19.27. HRMS (ESI+): Calcd forC₂₅H₃₁N₃O₄ [M+H]⁺: 438.5393, Found: 438.2412.

Tert-butyl(S)-2-(3-(6-(benzyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4f)

4f was synthesized using general procedure 3. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 4f (59 mg,39%), a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.54 (d, J=1.6 Hz, 1H),8.10 (dd, J=8.6, 1.8 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.80 (t, J=8.5 Hz,1H), 7.53-7.47 (m, 1H), 7.46-7.39 (m, 2H), 7.37-7.33 (m, 1H), 7.29 (dd,J=8.7, 2.6 Hz, 1H), 5.31-5.08 (m, 2H), 5.21 (s, 2H), 3.83-3.66 (m, 1H),3.62-3.48 (m, 1H), 2.46-2.33 (m, 1H), 2.26-2.11 (m, 2H), 2.09-1.95 (m,1H), 1.48 (s, 3H), 1.31 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 180.70,168.63, 158.23, 153.71, 136.71, 136.18, 130.57, 128.79, 128.71, 128.26,127.88, 127.69, 124.55, 122.08, 120.07, 107.39, 80.60, 70.26, 54.02,46.52, 32.57, 28.54, 28.30, 23.87. HRMS (ESI+): Calcd for C₂₈H₂₉N₃O₄[M+Na]⁺: 494.5373, Found: 494.2094.

Tert-butyl(S)-2-(3-(6-((4-methylbenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4g)

4g was synthesized using general procedure 3. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 4g (30 mg,13%), a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 8.50 (d, J=4.6 Hz, 1H),8.11-8.02 (m, 1H), 7.85-7.73 (m, 2H), 7.36 (d, J=7.7 Hz, 2H), 7.27-7.18(m, 5H), 5.24-5.04 (m, 1H), 5.14 (s, 2H), 3.78-3.67 (m, 1H), 3.63-3.45(m, 1H), 2.47-2.38 (m, 1H), 2.37 (s, 3H), 2.24-2.12 (m, 2H), 2.06-1.96(m, 1H), 1.46 (s, 3H), 1.29 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 180.69,168.65, 158.32, 153.77, 138.11, 136.21, 133.65, 130.54, 129.49, 128.67,127.87, 127.68, 127.53, 124.51, 122.00, 120.16, 107.33, 80.66, 70.22,54.03, 46.54, 32.59, 28.55, 28.31, 23.89, 21.37. HRMS (ESI+): Calcd forC₂₉H₃₁N₃O₄ [M+H]⁺: 508.5639, Found: 508.2244.

Tert-butyl(S)-2-(3-(6-(tosyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4h)

4h was synthesized using general procedure 3. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 4h (15 mg,13%), a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J=6.4 Hz, 1H),8.14 (t, J=8.5 Hz, 1H), 7.90-7.77 (m, 2H), 7.74 (d, J=8.0 Hz, 2H),7.55-7.48 (m, 1H), 7.35-7.29 (m, 2H), 7.19-7.11 (m, 1H), 5.26-5.07 (m,1H), 3.79-3.63 (m, 1H), 3.62-3.48 (m, 1H), 2.48-2.34 (m, 1H), 2.45 (s,3H), 2.24-2.12 (m, 2H), 2.07-1.98 (m, 1H), 1.47 (s, 3H), 1.29 (s, 6H).¹³C NMR (101 MHz, CDCl₃) δ 181.06, 168.20, 153.70, 148.49, 145.71,134.90, 132.42, 131.61, 130.85, 129.98, 128.85, 128.66, 127.81, 125.10,124.95, 124.75, 122.29, 122.15, 120.15, 80.69, 53.98, 46.52, 36.75,32.57, 28.54, 28.53, 28.28, 24.81, 23.87, 21.88. HRMS (ESI+): Calcd forC₂₈H₂₉N₃O₆S [M+Na]⁺: 558.6011, Found: 558.1710.

Tert-butyl(2S,3S)-3-hydroxy-2-(3-(6-(pentyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4i)

4i was synthesized using general procedure 3. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 41 (232 mg,90%), a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.51-8.43 (m, 1H),8.10-7.98 (m, 1H), 7.84-7.68 (m, 2H), 7.22-7.06 (m, 2H), 5.20-4.97 (m,1H), 4.65-4.58 (m, 1H), 4.07 (t, J=6.5 Hz, 2H), 3.85-3.71 (m, 2H),2.41-2.29 (m, 1H), 2.09-2.05 (m, 1H), 1.85 (p, J=6.8 Hz, 2H), 1.51-1.24(m, 11H), 0.95 (t, J=7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 178.14,168.64, 158.55, 153.74, 136.20, 130.25, 128.28, 127.80, 127.43, 124.22,121.33, 119.95, 106.58, 80.80, 77.29, 76.97, 76.66, 76.10, 68.12, 62.34,44.28, 32.15, 28.85, 28.36, 28.21, 28.12, 22.43, 13.99. HRMS (ESI+):Calcd for C₂₆H₃₃N₃O₅ [M+Na]⁺: 490.5471, Found: 490.2309.

Tert-butyl(2S,3S)-3-hydroxy-2-(3-(6-isobutoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4j)

4j was synthesized using general procedure 3. Purification on a silicagel column with 40-70% ethyl acetate in hexanes produced 4j (52 mg,49%), a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=22.8 Hz, 1H),8.07-7.97 (m, 1H), 7.83-7.72 (m, 2H), 7.23-7.06 (m, 2H), 5.23-4.96 (m,1H), 4.62 (d, J=6.9 Hz, 1H), 3.90-3.70 (m, 4H), 2.41-2.33 (m, 1H),2.23-2.01 (m, 2H), 1.56-1.21 (m, 12H), 1.07 (d, J=6.7 Hz, 6H). ¹³C NMR(101 MHz, CDCl₃) δ 178.23, 168.64, 158.67, 153.88, 136.23, 130.26,128.28, 127.83, 127.46, 124.20, 121.28, 120.00, 106.58, 80.92, 77.34,77.02, 76.70, 76.03, 74.48, 62.36, 44.36, 32.13, 28.38, 28.24, 28.14,19.30. HRMS (ESI+): Calcd for C₂₅H₃₁N₃O₅ [M+Na]⁺: 476.5205, Found:476.2168.

(S)-2-(3-(6-butoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5a)

5a was synthesized using general procedure 4 and carried forward withoutpurification.

(S)-2-(3-(6-(pentyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5b)

5b was synthesized using general procedure 4 and carried forward withoutpurification.

(S)-2-(3-(6-(hexyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5c)

5c was synthesized using general procedure 4 and carried forward withoutpurification.

(S)-2-(3-(6-(heptyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5d)

5d was synthesized using general procedure 4 and carried forward withoutpurification.

(S)-2-(3-(6-isobutoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5e)

5e was synthesized using general procedure 4 and carried forward withoutpurification.

(S)-2-(3-(6-(benzyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5f)

5f was synthesized using general procedure 4 and carried forward withoutpurification.

(S)-2-(3-(6-((4-methylbenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5g)

5g was synthesized using general procedure 4 and carried forward withoutpurification.

(S)-2-(3-(6-(tosyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5h)

5h was synthesized using general procedure 4 and carried forward withoutpurification.

(2S,3S)-3-hydroxy-2-(3-(6-(pentyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5i)

5i was synthesized using general procedure 4 and carried forward withoutpurification.

(2S,3S)-3-hydroxy-2-(3-(6-isobutoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (5j)

5j was synthesized using general procedure 4 and carried forward withoutpurification.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(butyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6a)

6a was synthesized using general procedure 5. Purification on a silicagel column with 10-30% ethyl acetate in hexanes produced 6a (25 mg,67%), a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=1.6 Hz, 1H),8.07 (dd, J=8.6, 1.7 Hz, 1H), 7.80 (dd, J=16.6, 8.8 Hz, 2H), 7.22-7.12(m, 2H), 5.63 (dd, J=7.9, 4.6 Hz, 1H), 4.11 (t, J=6.5 Hz, 2H), 3.95-3.89(m, 1H), 3.87-3.76 (m, 1H), 2.52-2.41 (m, 1H), 2.33-2.17 (m, 2H),2.12-2.00 (m, 1H), 1.85 (p, J=6.7 Hz, 2H), 1.57-1.39 (m, 18H), 1.01 (t,J=7.4 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 168.69, 158.66, 153.77,150.53, 136.34, 130.43, 128.49, 128.03, 127.48, 124.57, 120.03, 106.77,82.36, 79.72, 67.99, 49.61, 31.41, 28.28, 19.47, 14.02. HRMS (ESI+):Calcd for C₃₁H₄₁N₅O₆[M+H]⁺: 560.6951, Found: 580.3122.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(pentyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6b)

6b was synthesized using general procedure 5. Purification on a silicagel column with 10-30% ethyl acetate in hexanes produced 6b (23 mg,63%), a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=1.6 Hz, 1H),8.07 (dd, J=8.6, 1.7 Hz, 1H), 7.80 (dd, J=17.4, 8.8 Hz, 2H), 7.21-7.13(m, 2H), 5.63 (dd, J=7.9, 4.5 Hz, 1H), 4.09 (t, J=6.6 Hz, 2H), 3.95-3.88(m, 1H), 3.87-3.77 (m, 1H), 2.53-2.41 (m, 1H), 2.32-2.15 (m, 2H),2.11-2.02 (m, 1H), 1.90-1.82 (m, 2H), 1.79-1.68 (m, 1H), 1.60-1.36 (m,24H), 0.95 (t, J=7.1 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 178.98, 168.66,158.63, 154.08, 150.58, 136.32, 130.41, 128.47, 128.02, 127.47, 124.54,121.74, 120.01, 106.75, 82.28, 79.76, 68.27, 55.52, 49.60, 36.78, 29.03,28.40, 28.26, 28.12, 24.82, 23.49, 22.61, 14.17. HRMS (ESI+): Calcd forC₃₂H₄₃N₅O₆ [M+H]⁺: 594.7217, Found: 594.3323.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(hexyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6c)

6c was synthesized using general procedure 5. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 6c (25 mg,66%), a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.51 (d, J=1.6 Hz, 1H),8.07 (dd, J=8.5, 1.7 Hz, 1H), 7.80 (dd, J=20.7, 8.8 Hz, 2H), 7.19 (dd,J=8.9, 2.5 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 5.64 (d, J=6.3 Hz, 1H), 4.09(t, J=6.6 Hz, 2H), 3.93 (dd, J=11.5, 6.4 Hz, 1H), 3.83 (s, 1H),2.51-2.41 (m, 1H), 2.34-2.16 (m, 2H), 2.06 (dd, J=12.9, 6.2 Hz, 1H),1.91-1.79 (m, 2H), 1.64-1.29 (m, 27H), 0.98-0.88 (m, 3H). ¹³C NMR (126MHz, CDCl₃) δ 178.93, 168.67, 158.64, 136.31, 130.42, 128.03, 127.48,124.54, 120.02, 106.72, 68.29, 55.54, 49.64, 31.74, 29.31, 28.27, 25.93,22.78, 14.21. HRMS (ESI+): Calcd for C₃₃H₄₅N₅O₆ [M+H]⁺: 608.7482, Found:608.3447.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(heptyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6d)

6d was synthesized using general procedure 5. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 6d (14 mg,59%), a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=1.6 Hz, 1H),8.05 (dd, J=8.6, 1.7 Hz, 1H), 7.78 (dd, J=17.1, 8.8 Hz, 2H), 7.21-7.11(m, 2H), 5.61 (dd, J=7.9, 4.5 Hz, 1H), 4.08 (t, J=6.5 Hz, 2H), 3.97-3.88(m, 1H), 3.85-3.75 (m, 1H), 2.51-2.39 (m, 1H), 2.31-2.15 (m, 2H), 2.05(dd, J=12.8, 6.3 Hz, 1H), 1.84 (p, J=6.7 Hz, 2H), 1.67-1.17 (m, 26H),0.92-0.83 (m, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 178.85, 168.54, 162.00,158.51, 150.38, 136.19, 130.29, 128.33, 127.89, 127.35, 124.40, 121.58,119.89, 106.59, 82.27, 79.59, 77.60, 77.28, 77.02, 76.77, 68.15, 55.37,49.49, 36.63, 31.80, 29.71, 29.20, 29.08, 28.12, 26.07, 22.63, 14.11.HRMS (ESI+): Calcd for C₃₄H₄₇N₅O₆ [M+H]⁺: 622.7748, Found: 622.3606.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-isobutoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6e)

6e was synthesized using general procedure 5. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 6e (34 mg,65%), a clear oil. ¹H NMR (500 MHz, CDCl₃) δ d) δ 8.51 (d, J=1.7 Hz,1H), 8.07 (dd, J=8.5, 1.7 Hz, 1H), 7.80 (dd, J=22.6, 8.8 Hz, 2H), 7.20(dd, J=9.0, 2.5 Hz, 1H), 7.14 (d, J=2.5 Hz, 1H), 5.63 (dd, J=8.0, 4.6Hz, 1H), 3.97-3.88 (m, 1H), 3.95-3.82 (m, 3H), 2.50-2.42 (m, 1H),2.29-2.14 (m, 3H), 2.12-1.97 (m, 1H), 1.55-1.38 (m, 20H), 1.08 (d, J=6.7Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 178.97, 168.67, 162.11, 158.73,153.76, 150.52, 136.32, 130.40, 128.45, 128.01, 127.46, 124.53, 121.71,120.03, 106.75, 82.36, 79.72, 74.64, 55.51, 49.61, 28.40, 28.25, 19.46.HRMS (ESI+): Calcd for C₃₁H₄₁N₅O₆ [M+H]⁺: 580.6951, Found: 580.3123.

Tert-butyl(S,E)-((2-(3-(6-(benzyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate(6f)

6e was synthesized using general procedure 5. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 6e (12 mg,40%), a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J=1.6 Hz, 1H),8.09 (dd, J=8.6, 1.7 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.6 Hz,1H), 7.53-7.48 (m, 2H), 7.45-7.40 (m, 2H), 7.39-7.33 (m, 1H), 7.30-7.25(m, 2H), 5.64 (dd, J=7.9, 4.5 Hz, 1H), 5.21 (s, 2H), 3.97-3.88 (m, 1H),3.86-3.75 (m, 1H), 2.55-2.40 (m, 1H), 2.31-2.16 (m, 2H), 2.10-2.00 (m,1H), 1.57-1.33 (m, 18H). ¹³C NMR (101 MHz, CDCl₃) δ 179.02, 168.64,158.24, 153.74, 150.73, 136.74, 136.20, 130.58, 128.82, 128.71, 128.29,128.02, 127.72, 127.60, 124.65, 122.06, 120.03, 107.40, 82.44, 79.65,77.36, 55.53, 49.61, 32.07, 29.85, 28.27, 22.84, 14.26. HRMS (ESI+):Calcd for C₃₄H₃₉N₅O₆ [M+H]⁺: 614.7113, Found: 614.2990.

Tert-butyl(S,E)-(((tert-butoxycarbonyl)amino)(2-(3-(6-((4-methylbenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6g)

6g was synthesized using general procedure 5. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 6g (4 mg, 27%),a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 8.06 (dd, J=8.6,1.7 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.36 (d,J=8.0 Hz, 2H), 7.24-7.18 (m, 4H), 5.62 (dd, J=7.8, 4.6 Hz, 1H), 5.15 (s,2H), 3.95-3.86 (m, 1H), 3.85-3.77 (m, 1H), 2.50-2.38 (m, 1H), 2.36 (s,3H), 2.33-2.14 (m, 2H), 2.10-1.99 (m, 1H), 1.49-1.38 (m, 18H). HRMS(ESI+): Calcd for C₃₅H₄₁N₅O₆ [M+H]⁺: 628.3154, Found: 628.7379.

(S,E)-6-(5-(1-(N,N′-bis(tert-butoxycarbonyl)carbamimidoyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)naphthalen-2-yl4-methylbenzenesulfonate (6h)

6h was synthesized using general procedure 5. Purification on a silicagel column with 15-30% ethyl acetate in hexanes produced 6h (7 mg, 61%),a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.57 (d, J=1.6 Hz, 1H), 8.14 (dd,J=8.6, 1.6 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H),7.78-7.70 (m, 2H), 7.52 (d, J=2.3 Hz, 1H), 7.34-7.27 (m, 2H), 7.16 (dd,J=8.9, 2.4 Hz, 1H), 5.64 (dd, J=7.9, 4.6 Hz, 1H), 3.97-3.89 (m, 1H),3.86-3.77 (m, 1H), 2.54-2.46 (m, 1H), 2.45 (s, 3H), 2.33-2.14 (m, 2H),2.10-2.01 (m, 1H), 1.46 (s, 18H). ¹³C NMR (126 MHz, CDCl₃) δ 179.44,168.24, 162.14, 153.86, 150.35, 148.51, 145.69, 134.92, 132.53, 131.63,130.85, 129.99, 128.75, 128.70, 127.96, 125.09, 124.82, 122.25, 120.15,82.48, 79.87, 55.53, 49.64, 31.39, 29.84, 28.25, 24.18, 21.88. HRMS(ESI+): Calcd for C₃₄H₃₉N₅O₈S [M+H]⁺: 678.7751, Found: 678.2600.

Tert-butyl((E)-((tert-butoxycarbonyl)amino)((2S,3S)-3-hydroxy-2-(3-(6-(pentyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6i)

6i was synthesized using general procedure 5. Purification on a silicagel column with 20-40% ethyl acetate in hexanes produced 6i (34 mg,66%), a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=1.6 Hz, 1H),8.02 (dd, J=8.6, 1.7 Hz, 1H), 7.78-7.70 (m, 2H), 7.20-7.08 (m, 2H),5.62-5.56 (m, 1H), 4.69 (s, 1H), 4.05 (t, J=6.5 Hz, 2H), 4.02-3.93 (m,2H), 2.40-2.33 (m, 1H), 2.22-2.08 (m, 1H), 1.89-1.78 (m, 2H), 1.45 (d,J=14.5 Hz, 21H), 0.95 (t, J=7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ176.57, 168.65, 158.57, 136.24, 130.31, 128.30, 127.97, 127.39, 124.34,121.35, 119.93, 106.60, 82.53, 79.86, 77.58, 77.27, 77.01, 76.76, 74.93,68.14, 63.41, 46.92, 31.93, 29.70, 28.89, 28.42, 28.26, 28.10, 28.04,22.70, 22.48, 14.12, 14.03. HRMS (ESI+): Calcd for C₃₂H₄₃N₅O₇ [M+H]⁺:610.7211, Found: 610.3248.

Tert-butyl((Z)-((tert-butoxycarbonyl)amino)((2S,3S)-3-hydroxy-2-(3-(6-isobutoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6j)

6j was synthesized using general procedure 5. Purification on a silicagel column with 20-40% ethyl acetate in hexanes produced 6j (32 mg,70%), a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 8.48 (s, 1H), 8.04 (dd,J=8.6, 1.4 Hz, 1H), 7.78 (dd, J=17.2, 8.8 Hz, 2H), 7.21-7.17 (m, 1H),7.13 (s, 1H), 5.57 (s, 1H), 4.69 (s, 1H), 4.05-3.96 (m, 2H), 3.84 (d,J=6.5 Hz, 2H), 2.38 (dq, J=12.9, 8.4, 6.5 Hz, 1H), 2.14 (ddd, J=13.2,8.1, 5.3 Hz, 2H), 1.47 (d, J=17.8 Hz, 22H), 1.07 (d, J=6.7 Hz, 7H). ¹³CNMR (126 MHz, CDCl₃) δ 176.79, 168.76, 158.79, 153.93, 136.38, 130.43,128.42, 128.12, 127.51, 124.47, 121.44, 120.07, 106.75, 77.73, 77.41,77.16, 76.91, 74.97, 74.64, 63.57, 47.12, 32.07, 29.84, 29.80, 29.51,28.40, 28.24, 22.84, 19.45, 14.26. HRMS (ESI+): Calcd for C₃₁H₄₁N₅O₇[M+H]⁺: 596.6945, Found: 596.3020.

Example 59:(S)-amino(2-(3-(6-(butyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7a, compound 56A)

7a was synthesized using general procedure 4 and isolated as a lightyellow tinted (6 mg, 42%). ¹H NMR (400 MHz, CD₃OD) δ 8.50 (d, J=1.6 Hz,1H), 8.03 (dd, J=8.6, 1.7 Hz, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.30 (d,J=2.4 Hz, 1H), 7.21 (dd, J=9.0, 2.4 Hz, 1H), 5.46 (dd, J=7.7, 1.9 Hz,1H), 4.14 (t, J=6.4 Hz, 2H), 3.85-3.77 (m, 1H), 3.68-3.61 (m, 1H),2.64-2.47 (m, 2H), 2.29-2.19 (m, 1H), 2.18-2.07 (m, 1H), 1.88-1.80 (m,2H), 1.63-1.51 (m, 2H), 1.02 (t, J=7.4 Hz, 3H). ¹³C NMR (101 MHz, CD₃OD)δ 177.39, 168.45, 155.67, 150.38, 129.82, 127.35, 125.45, 123.51,120.94, 119.72, 118.77, 117.17, 106.28, 104.79, 67.51, 55.07, 30.98,22.91, 18.91, 12.73. HRMS (ESI+): Calcd for C₂₁H₂₅N₅O₂ [M+H]⁺: 380.4636,Found: 380.2069.

Example 60:(S)-amino(2-(3-(6-(pentyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7b, compound 12A)

7b was synthesized using general procedure 4 and isolated as a lightyellow tinted (5 mg, 95%). ¹H NMR (400 MHz, MeOD) δ 8.50 (d, J=1.6 Hz,1H), 8.03 (dd, J=8.5, 1.7 Hz, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.30 (d,J=2.4 Hz, 1H), 7.22 (dd, J=9.0, 2.4 Hz, 1H), 5.47 (dd, J=7.8, 2.0 Hz,1H), 4.13 (t, J=6.4 Hz, 2H), 3.85-3.77 (m, 1H), 3.69-3.60 (m, 2H),2.64-2.48 (m, 2H), 2.31-2.21 (m, 1H), 2.19-2.05 (m, 1H), 1.87 (dq,J=8.1, 6.5 Hz, 2H), 1.57-1.26 (m, 6H), 0.98 (t, J=7.2 Hz, 3H). ¹³C NMR(126 MHz, MeOD) δ 178.88, 169.89, 160.22, 157.10, 137.94, 131.29,129.73, 128.80, 124.97, 122.40, 121.18, 107.69, 69.23, 56.51, 49.46,32.74, 30.05, 29.45, 24.35, 23.56, 14.39. HRMS (ESI+): Calcd forC₂₂H₂₇N₅O₂ [M+H]⁺: 394.4900, Found: 394.2237.

Example 61:(S)-amino(2-(3-(6-(hexyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7c, compound 16A)

7c was synthesized using general procedure 4 and isolated as a lightyellow tinted solid (14 mg, 96%). ¹H NMR (400 MHz, MeOD) δ 8.51-8.46 (m,1H), 8.00 (dd, J=8.5, 1.6 Hz, 1H), 7.85 (d, J=8.7 Hz, 2H), 7.29-7.25 (m,1H), 7.19 (dd, J=9.0, 2.4 Hz, 1H), 5.44 (dd, J=7.8, 2.0 Hz, 1H), 4.11(t, J=6.4 Hz, 2H), 3.81-3.73 (m, 1H), 3.66-3.55 (m, 1H), 2.61-2.46 (m,2H), 2.26-2.19 (m, 1H), 2.14-2.06 (m, 1H), 1.88-1.80 (m, 2H), 1.56-1.47(m, 2H), 1.37 (dtd, J=8.2, 4.4, 3.0 Hz, 4H), 0.97-0.83 (m, 3H). ¹³C NMR(101 MHz, MeOD) δ 178.84, 169.91, 160.23, 157.12, 137.95, 131.28,129.74, 128.80, 124.97, 122.40, 121.17, 107.74, 69.27, 56.51, 49.64,49.43, 49.21, 49.00, 48.79, 48.57, 48.36, 32.79, 32.74, 30.31, 26.92,24.35, 23.69, 14.37. HRMS (ESI+): Calcd for C₂₃H₂₉N₅O₂ [M+H]⁺: 408.5166,Found: 408.2408.

Example 62:(S)-amino(2-(3-(6-(heptyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7d, compound 13A)

7d was synthesized using general procedure 4 and isolated as a lightyellow tinted solid (8 mg, 78%). ¹H NMR (500 MHz, MeOD) δ 8.51-8.47 (m,1H), 8.02 (dd, J=8.5, 1.5 Hz, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.44 (s, 1H),7.29 (d, J=2.1 Hz, 1H), 7.21 (dd, J=8.9, 2.3 Hz, 1H), 5.47 (d, J=7.2 Hz,1H), 4.12 (t, J=6.4 Hz, 2H), 3.80 (d, J=7.6 Hz, 1H), 3.65 (t, J=8.4 Hz,1H), 2.54 (dt, J=31.0, 6.3 Hz, 2H), 2.30-2.20 (m, 1H), 2.12 (d, J=7.2Hz, 1H), 1.87-1.79 (m, 2H), 1.56-1.48 (m, 2H), 1.45-1.28 (m, 7H),0.95-0.88 (m, 3H). ¹³C NMR (126 MHz, MeOD) δ 178.87, 169.88, 160.20,157.10, 137.93, 131.29, 129.72, 128.80, 124.97, 122.39, 121.16, 107.70,69.24, 56.52, 32.99, 32.75, 30.34, 30.23, 27.20, 24.35, 23.68, 14.41.HRMS (ESI+): Calcd for C₂₄H₃₁N₅O₂ [M+H]⁺: 422.5432, Found: 422.2564.

Example 63:(S)-amino(2-(3-(6-isobutoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7e, compound 14A)

7e was synthesized using general procedure 4 and isolated as a lightyellow tinted solid (17 mg, 99%). ¹H NMR (500 MHz, MeOD δ 8.50 (s, 1H),8.02 (dd, J=8.5, 1.3 Hz, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.44 (s, 2H), 7.29(d, J=2.1 Hz, 1H), 7.22 (dd, J=8.9, 2.2 Hz, 1H), 5.47 (d, J=7.0 Hz, 1H),3.90 (d, J=6.4 Hz, 2H), 3.80 (dd, J=17.0, 8.8 Hz, 1H), 3.64 (q, J=9.1Hz, 1H), 2.63-2.54 (m, 1H), 2.54-2.47 (m, 1H), 2.24 (s, 1H), 2.14 (dq,J=13.0, 6.5 Hz, 2H), 1.09 (d, J=6.7 Hz, 6H). ¹³C NMR (126 MHz, MeOD) δ178.87, 169.88, 160.27, 157.10, 137.92, 131.29, 129.72, 128.80, 124.96,122.39, 121.13, 107.74, 75.61, 56.54, 49.51, 49.34, 49.17, 49.00, 48.83,48.66, 48.49, 32.77, 29.51, 24.37, 19.57. HRMS (ESI+): Calcd forC₂₁H₂₅N₅O₂ [M+H]⁺: 380.4634, Found: 380.2109.

Example 64:(S)-amino(2-(3-(6-(benzyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7f, compound 73A)

7f was synthesized using general procedure 4 and isolated as a lightyellow tinted solid (7 mg, 95%). ¹H NMR (500 MHz, CD₃OD) δ 8.52 (d,J=1.6 Hz, 1H), 8.03 (dd, J=8.6, 1.7 Hz, 1H), 7.89 (dd, J=14.2, 8.8 Hz,2H), 7.53-7.49 (m, 2H), 7.43-7.37 (m, 3H), 7.36-7.28 (m, 2H), 5.49-5.45(m, 1H), 5.24 (s, 2H), 3.84-3.79 (m, 1H), 3.68-3.60 (m, 1H), 2.64-2.54(m, 1H), 2.53-2.47 (m, 1H), 2.28-2.20 (m, 1H), 2.16-2.06 (m, 1H). ¹³CNMR (126 MHz, CD₃OD) δ 178.88, 169.84, 159.78, 157.08, 138.29, 137.79,131.42, 129.89, 129.57, 129.04, 128.88, 128.80, 128.71, 125.04, 122.62,121.19, 108.46, 71.17, 56.53, 32.76, 24.36. HRMS (ESI+): Calcd forC₂₄H₂₃N₅O₂ [M+H]⁺: 414.4797, Found: 414.1926.

Example 65:(S)-amino(2-(3-(6-((4-methylbenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7g, compound 64A)

7g was synthesized using general procedure 4 and isolated as a lightyellow tinted solid (3 mg, 100%). ¹H NMR (400 MHz, CD₃OD) δ 8.50 (d,J=15.9 Hz, 1H), 8.06-7.96 (m, 1H), 7.88 (dd, J=21.9, 8.7 Hz, 1H), 7.76(d, J=8.9 Hz, 1H), 7.40 (d, J=20.1 Hz, 4H), 7.31-7.20 (m, 1H), 7.16 (d,J=8.2 Hz, 1H), 5.49 (d, J=1.3 Hz, 1H), 5.46 (d, J=6.9 Hz, 1H), 5.19 (s,1H), 3.85-3.75 (m, 1H), 3.68-3.58 (m, 1H), 2.65-2.46 (m, 2H), 2.35 (s,3H), 2.29-2.19 (m, 1H), 2.18-2.06 (m, 1H). HRMS (ESI+): Calcd forC₂₅H₂₅N₅O₂ [M+H]⁺: 428.5062, Found: 428.2083.

(S)-amino(2-(3-(6-(tosyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7h, compound)

7h was synthesized using general procedure 4 and isolated as a lightyellow tinted solid (7 mg, 100%). ¹H NMR (400 MHz, CD₃OD) δ 8.59 (dd,J=1.6, 0.8 Hz, 1H), 8.11 (dd, J=8.6, 1.7 Hz, 1H), 7.99-7.89 (m, 2H),7.75-7.70 (m, 2H), 7.56 (d, J=2.4 Hz, 1H), 7.43-7.37 (m, 2H), 7.20 (dd,J=8.9, 2.4 Hz, 1H), 5.46 (dd, J=7.9, 2.0 Hz, 1H), 3.78 (td, J=9.2, 2.6Hz, 1H), 3.66-3.58 (m, 1H), 2.62-2.54 (m, 1H), 2.52-2.45 (m, 1H), 2.43(s, 3H), 2.27-2.17 (m, 1H), 2.15-2.03 (m, 1H). HRMS (ESI+): Calcd forC₂₄H₂₃N₅O₄S [M+H]⁺: 478.5435, Found: 478.1561.

Example 66:Amino((2S,3S)-3-hydroxy-2-(3-(6-(pentyloxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7i, compound 14B)

7i was synthesized using general procedure 4 and isolated as a lightyellow tinted solid (73 mg, 100%). ¹H NMR (500 MHz, CD₃OD) δ 8.51-8.50(m, 1H), 8.03 (dd, J=8.5, 1.6 Hz, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.50 (s,1H), 7.30 (d, J=2.3 Hz, 1H), 7.22 (dd, J=9.0, 2.4 Hz, 1H), 5.25 (s, 1H),4.82 (d, J=3.5 Hz, 1H), 4.13 (t, J=6.5 Hz, 2H), 3.88-3.80 (m, 2H),2.29-2.16 (m, 2H), 1.88-1.84 (m, 2H), 1.57-1.49 (m, 2H), 1.47-1.42 (m,2H), 0.98 (t, J=7.2 Hz, 3H). ¹³C NMR (126 MHz, CD₃OD) δ 176.68, 170.03,160.26, 157.61, 137.98, 131.30, 129.73, 128.85, 128.82, 124.96, 122.30,121.20, 107.72, 76.01, 69.24, 64.87, 49.51, 49.49, 49.45, 49.34, 49.28,49.17, 49.11, 49.00, 48.94, 48.83, 48.66, 48.49, 47.41, 32.52, 30.04,29.45, 23.55, 14.38. HRMS (ESI+): Calcd for C₂₂H₂₇N₅O₃ [M+H]⁺: 410.4894,Found: 410.2204.

Example 67:Amino((2S,3S)-3-hydroxy-2-(3-(6-isobutoxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7j, compound 15A)

7j was synthesized using general procedure 4 and isolated as a lightyellow tinted solid (9 mg, 62%). ¹H NMR (500 MHz, MeOD) δ 8.50 (s, 1H),8.04-7.98 (m, 1H), 7.88 (d, J=7.9 Hz, 2H), 7.51 (s, 1H), 7.29 (d, J=1.9Hz, 1H), 7.22 (dd, J=8.9, 2.1 Hz, 1H), 5.25 (s, 1H), 4.81 (d, J=2.9 Hz,1H), 3.93-3.74 (m, 4H), 2.29-2.10 (m, 3H), 1.09 (d, J=6.7 Hz, 6H). ¹³CNMR (126 MHz, MeOD) δ 176.66, 170.01, 160.30, 157.59, 137.95, 131.31,129.72, 128.84, 128.83, 124.94, 122.28, 121.14, 107.76, 76.01, 75.62,64.85, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 47.43, 32.52,29.50, 19.56. HRMS (ESI+): Calcd for C₂₁H₂₅N₅O₃ [M+H]: 396.4628, Found:396.2020.

N′,6-dihydroxy-2-naphthimidamide (8)

8 was synthesized using general procedure 1 and isolated as a mixture ofenantiomers and a beige solid (293 mg, 49%). ¹H NMR (400 MHz, CD₃OD) δ8.02 (d, J=1.4 Hz, 1H), 7.85-7.80 (m, 1H), 7.66-7.61 (m, 2H), 7.15 (d,J=1.7 Hz, 1H), 7.11 (s, 1H). ¹³C NMR (101 MHz, CD₃OD) δ 188.77, 157.50,137.14, 131.85, 131.11, 129.37, 129.14, 128.70, 128.27, 127.36, 126.63,125.40, 124.94, 120.30, 119.93, 109.81. HRMS (ESI+): Calcd forC₁₁H₁₀N₂O₂ [M+H]⁺: 203.2172, Found: 203.0821.

Tert-butyl(S)-2-(3-(6-hydroxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(9)

9 was synthesized using general procedure 2 and isolated as a lightyellow solid (218 mg, 58%). ¹H NMR (1:1 rotamer ratio, 400 MHz, CDCl₃) δ1H NMR (400 MHz, Chloroform-d) δ 8.50 (s, 1H), 8.06 (d, J=8.6 Hz, 1H),7.93 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.78-7.71 (m, 1H), 7.70 (s, 1H),7.50 (d, J=8.7 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.20 (s, 1H), 7.16 (d,J=8.9 Hz, 1H), 7.00 (d, J=7.3 Hz, 1H), 6.91 (s, 1H), 5.30-5.07 (m, 1H),3.76 (d, J=7.9 Hz, 1H), 3.69-3.50 (m, 1H), 2.43 (d, J=12.3 Hz, 1H),2.26-2.09 (m, 2H), 2.07-1.97 (m, 1H), 1.43 (d, J=86.6 Hz, 9H). ¹³C NMR(101 MHz, CDCl₃) δ 180.55, 179.23, 168.53, 156.15, 156.04, 155.13,154.20, 136.45, 136.08, 130.82, 130.55, 128.20, 128.05, 127.51, 127.28,126.52, 124.34, 123.76, 121.36, 120.43, 119.20, 118.80, 109.78, 109.35,81.64, 81.25, 54.28, 54.07, 47.15, 46.58, 32.49, 31.89, 28.63, 28.34,24.41, 23.85. HRMS (ESI+): Calcd for C₂₁H₂₃N₃O₄ [M+Na]⁺: 404.4148,Found: 404.1569.

(S)-2-(3-(6-hydroxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-iumchloride (10)

10 was synthesized using genera procedure 3 and isolated as a lightyellow solid (160 mg, 96%). ¹H NMR (400 MHz, CD₃OD) δ 8.55-8.52 (m, 1H),8.02 (dd, J=8.6, 1.7 Hz, 1H), 7.88-7.83 (m, 1H), 7.78 (dt, J=8.7, 0.7Hz, 1H), 7.17 (d, J=8.2 Hz, 2H), 5.21 (t, J=7.8 Hz, 1H), 3.68-3.51 (m,2H), 2.70 (dd, J=13.4, 5.7 Hz, 1H), 2.53-2.42 (m, 1H), 2.35-2.24 (m,2H). ¹³C NMR (101 MHz, CD₃OD) δ 175.79, 170.13, 158.68, 138.23, 131.58,129.18, 129.11, 128.29, 124.77, 121.38, 120.62, 110.17, 55.66, 49.64,49.50, 49.43, 49.28, 49.21, 49.00, 48.79, 48.57, 48.36, 47.42, 30.23,24.53. HRMS (ESI+): Calcd for C₁₆H₁₅N₃O₂ [M+H]⁺: 282.3171, Found:282.1243.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-hydroxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(11)

11 was synthesized using general procedure 4 and isolated as a lightyellow solid (90 mg, 35%). ¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.65(d, J=8.0 Hz, 2H), 7.39 (t, J=9.8 Hz, 2H), 7.02 (d, J=2.4 Hz, 1H), 6.88(d, J=2.3 Hz, 1H), 5.65 (dd, J=8.0, 4.5 Hz, 1H), 3.97-3.86 (m, 1H),3.86-3.76 (m, 1H), 2.54-2.44 (m, 1H), 2.31-2.2.25 (m, 1H), 2.17-1.99 (m,2H), 1.48 (d, J=4.7 Hz, 20H). ¹³C NMR (101 MHz, CDCl₃) δ 177.92, 168.64,156.35, 154.15, 136.18, 130.38, 127.94, 127.57, 127.44, 126.56, 123.69,120.14, 119.02, 109.54, 81.69, 77.48, 77.36, 77.16, 76.84, 55.69, 49.85,31.50, 29.81, 28.22, 24.27. HRMS (ESI+): Calcd for C₂₇H₃₃N₅O₆[M+H]⁺:524.5888, Found: 524.2532.

Tert-butyl(S,E)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(3-methoxypropoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6k)

6k was synthesized using general procedure 5 and isolated as a clearresidue (3 mg, 9%).

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(4-methoxybutoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6l)

6l was synthesized using general procedure 5 and isolated as a clearresidue (5 mg, 14%). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=1.7 Hz, 1H),8.07 (dd, J=8.6, 1.7 Hz, 1H), 7.80 (dd, J=16.7, 8.8 Hz, 2H), 7.21-7.11(m, 2H), 5.63 (dd, J=7.9, 4.5 Hz, 1H), 4.13 (t, J=6.3 Hz, 2H), 3.97-3.89(m, 1H), 3.87-3.78 (m, 1H), 3.48 (t, J=6.3 Hz, 2H), 3.37 (s, 3H),2.52-2.41 (m, 1H), 2.29-2.17 (m, 2H), 2.11-2.00 (m, 1H), 1.97-1.88 (m,2H), 1.86-1.75 (m, 2H), 1.52-1.38 (m, 18H). HRMS (ESI+): Calcd forC₃₂H₄₃N₅O₇ [M+H]⁺: 610.7211, Found: 610.3275.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(cyclopentylmethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6m)

6m was synthesized using general procedure 5 and isolated as a clearresidue (2 mg, 6%).

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-((4-(trifluoromethyl)benzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6n)

6n was synthesized using general procedure 5 and isolated as a clearresidue (8 mg, 20%). ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J=1.6 Hz, 1H),8.08 (dd, J=8.6, 1.7 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.77 (d, J=8.7 Hz,1H), 7.66 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.2 Hz, 2H), 7.27 (dd, J=9.0,2.5 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 5.64 (dd, J=7.9, 4.6 Hz, 1H), 5.25(s, 2H), 3.95-3.89 (m, 1H), 3.87-3.78 (m, 1H), 2.51-2.43 (m, 1H),2.31-2.14 (m, 2H), 2.05-1.97 (m, 2H), 1.45 (s, 18H). HRMS (ESI+): Calcdfor C₃₅H₃₈F₃N₅O₆ [M+H]⁺: 682.7093, Found: 682.2889.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-((3-(trifluoromethyl)benzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6o)

6o was synthesized using general procedure 5 and isolated as a clearresidue (4 mg, 10%). HRMS (ESI+): Calcd for C₃₅H₃₈F₃N₅O₆ [M+H]⁺:682.7093, Found: 682.2889.

Tert-butyl(S,Z)-((2-(3-(6-((4-bromobenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate(6p)

6p was synthesized using general procedure 5 and isolated as a clearresidue (3 mg, 8%). ¹H NMR (400 MHz, CDCl₃) δ 8.57-8.49 (m, 1H),8.36-8.17 (m, 2H), 8.07 (dd, J=8.6, 1.7 Hz, 1H), 7.88-7.78 (m, 2H),7.56-7.46 (m, 3H), 7.42-7.35 (m, 2H), 5.29 (d, J=5.6 Hz, 1H), 5.16 (s,1H), 4.66 (s, 1H), 4.21-4.11 (m, 1H), 4.08-4.00 (m, 1H), 2.70-2.58 (m,1H), 2.55-2.41 (m, 1H), 2.30-2.19 (m, 2H), 1.57-1.45 (m, 17H). HRMS(ESI+): Calcd for C₂₄H₃₈BrN₅O₆ [M+H]⁺: 693.6074, Found: 693.2114.

Tert-butyl(S,Z)-((2-(3-(6-((3-bromobenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate(6q)

6q was synthesized using general procedure 5 and isolated as a clearresidue (2 mg, 5%). HRMS (ESI+): Calcd for C₃₄H₃₈BrN₅O₆ [M+K]⁺:731.6977, Found: 730.1707.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-((4-chlorobenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6r)

6r was synthesized using general procedure 5 and isolated as a clearresidue (4 mg, 10%). ¹H NMR (500 MHz, CDCl₃)¹H NMR (500 MHz, CDCl₃) δ8.53 (d, J=1.6 Hz, 1H), 8.09 (dd, J=8.5, 1.7 Hz, 1H), 7.82 (dd, J=34.8,8.8 Hz, 2H), 7.45-7.36 (m, 4H), 7.26 (dd, J=8.9, 2.5 Hz, 1H), 7.22 (d,J=2.5 Hz, 1H), 5.63 (dd, J=7.9, 4.7 Hz, 1H), 5.17 (s, 2H), 3.95-3.87 (m,1H), 3.85-3.77 (m, 1H), 2.53-2.40 (m, 1H), 2.30-2.19 (m, 2H), 2.08-2.02(m, 1H), 1.52-1.42 (m, 24H). ¹³C NMR (126 MHz, CDCl₃) δ 179.08, 168.59,157.96, 153.63, 148.81, 136.12, 135.25, 134.11, 130.68, 129.00, 128.78,128.02, 127.61, 124.73, 122.19, 119.89, 114.87, 107.43, 83.55, 77.73,69.49, 55.52, 49.62, 31.60, 31.22, 28.26, 28.13, 24.13, 21.18, 14.34.HRMS (ESI+): Calcd for C₃₄H₃₈ClN₅O₆ [M+H]⁺: 649.1564, Found: 649.16.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-((3-chlorobenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6s)

6s was synthesized using general procedure 5 and isolated as a clearresidue (7 mg, 19%). ¹H NMR (500 MHz, CDCl₃) δ 8.53 (d, J=1.5 Hz, 1H),8.09 (dd, J=8.6, 1.7 Hz, 1H), 7.82 (dd, J=34.9, 8.8 Hz, 2H), 7.50 (s,1H), 7.38-7.29 (m, 3H), 7.29-7.26 (m, 1H), 7.21 (d, J=2.5 Hz, 1H), 5.63(dd, J=7.9, 4.6 Hz, 1H), 5.17 (s, 2H), 3.95-3.88 (m, 1H), 3.85-3.77 (m,1H), 2.53-2.39 (m, 1H), 2.36-2.17 (m, 2H), 2.11-2.01 (m, 1H), 1.58-1.38(m, 22H). ¹³C NMR (126 MHz, CDCl₃) δ 178.92, 171.10, 168.44, 157.75,153.54, 150.39, 138.66, 135.96, 134.61, 130.55, 129.94, 128.66, 128.25,127.87, 127.49, 127.47, 125.42, 124.58, 122.07, 119.71, 107.27, 82.21,79.33, 69.24, 60.37, 55.37, 49.46, 28.30, 28.11, 28.07, 27.98, 21.03,14.19. HRMS (ESI+): Calcd for C₃₄H₃₈ClN₅O₆ [M+H]⁺: 649.1564, Found:649.17.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-((4-cyanobenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6t)

6t was synthesized using general procedure 5 and isolated as a clearresidue (4 mg, 11%). ¹H NMR (500 MHz, CDCl₃) δ 8.54 (d, J=1.6 Hz, 1H),8.09 (dd, J=8.7, 1.7 Hz, 1H), 7.88-7.77 (m, 2H), 7.72 (dd, J=8.2, 1.6Hz, 2H), 7.66-7.57 (m, 3H), 7.48 (dd, J=7.9, 0.8 Hz, 1H), 7.20 (d, J=2.5Hz, 1H), 5.39 (d, J=7.0 Hz, 1H), 5.27 (s, 2H), 4.06-3.99 (m, 1H),3.98-3.89 (m, 1H), 2.62-2.50 (m, 1H), 2.42-2.32 (m, 1H), 2.28-2.20 (m,1H), 2.17-2.09 (m, 1H), 1.59-1.40 (m, 21H).

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6u)

6u was synthesized using general procedure 5 and isolated as a clearresidue (10 mg, 24%). ¹H NMR (400 MHz, CDCl₃) δ 8.54-8.50 (m, 1H), 8.06(dd, J=8.6, 1.7 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H),7.29 (d, J=1.9 Hz, 1H), 7.16 (d, J=1.5 Hz, 2H), 7.14-7.11 (m, 1H), 7.06(dd, J=8.0, 1.9 Hz, 1H), 5.13-5.06 (m, 1H), 4.63 (d, J=4.5 Hz, 2H), 4.04(dd, J=8.6, 5.9 Hz, 1H), 3.19 (d, J=7.2 Hz, 1H), 2.37-2.27 (m, 1H),2.19-2.08 (m, 2H), 1.93-1.87 (m, 1H), 1.59 (d, J=1.4 Hz, 2H), 1.52 (s,2H), 1.27 (s, 3H), 1.26 (s, 3H), 1.25-1.20 (m, 24H), 1.17 (s, 3H), 1.14(s, 3H). HRMS (ESI+): Calcd for C₄₂H₅₃N₅O₆ [M+H]⁺: 742.9081, Found:724.4136.

Tert-butyl(S,Z)-((2-(3-(6-([1,1′-biphenyl]-4-ylmethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate(6v)

6v was synthesized using general procedure 5 and isolated as a clearresidue (3 mg, 8%). ¹H NMR (400 MHz, CDCl₃) δ 8.54-8.43 (m, 1H),8.36-8.29 (m, 1H), 8.18 (dd, J=8.9, 1.6 Hz, 1H), 8.06 (dd, J=8.6, 1.7Hz, 1H), 7.90-7.79 (m, 1H), 7.71-7.52 (m, 5H), 7.48-7.35 (m, 3H), 5.39(s, 1H), 5.36-5.32 (m, 1H), 5.26 (s, 1H), 4.28-4.19 (m, 1H), 4.17-1.09(m, 1H), 2.77-2.65 (m, 1H), 2.57-2.45 (m, 1H), 2.37-2.20 (m, 2H),1.70-1.40 (m, 16H). HRMS (ESI+): Calcd for C₄₀H₄₃N₅O₆ [M+H]⁺: 690.8073,Found: 690.3307.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(4-(trifluoromethyl)phenethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6w)

6w was synthesized using general procedure 5 and isolated as a clearresidue (4 mg, 10%). ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=15.6 Hz, 1H),8.27 (d, J=9.0 Hz, 1H), 8.17-8.11 (m, 1H), 8.07-7.98 (m, 1H), 7.89-7.70(m, 2H), 7.62-7.53 (m, 2H), 7.52-7.46 (m, 1H), 7.46-7.41 (m, 1H), 5.26(s, 1H), 4.36 (dt, J=29.7, 6.6 Hz, 2H), 4.25-4.18 (m, 1H), 4.17-4.09 (m,1H), 3.29-3.17 (m, 2H), 2.75-2.64 (m, 1H), 2.58-2.54 (m, 1H), 2.37-2.17(m, 2H), 1.69-1.39 (m, 21H). ¹⁹F NMR (376 MHz, CDCl₃) δ −62.47.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(3-(trifluoromethyl)phenethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)(6x)

6x was synthesized using general procedure 5 and isolated as a clearresidue (3 mg, 8%). ¹H NMR (400 MHz, CDCl₃) δ 8.55-8.44 (m, 1H), 8.29(d, J=8.9 Hz, 1H), 8.17-8.01 (m, 1H), 7.90-7.74 (m, 2H), 7.68 (s, 1H),7.60 (s, 1H), 7.55-7.49 (m, 2H), 7.49-7.42 (m, 2H), 5.38-5.28 (s, 1H),4.45-4.33 (m, 2H), 4.33-4.18 (m, 1H), 4.12-3.93 (m, 1H), 3.29-3.21 (m,2H), 2.82-2.72 (m, 1H), 2.64-2.50 (m, 1H), 2.38-2.23 (m, 2H), 1.78-1.38(m, 27H), ¹⁹F NMR (376 MHz, CDCl₃) δ −62.60, −62.63, −62.67.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(2-(trifluoromethyl)phenethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6y)

6y was synthesized using general procedure 5 and isolated as a clearresidue (2 mg, 5%). ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=14.8 Hz, 1H),8.28 (d, J=9.0 Hz, 1H), 8.15 (dd, J=8.9, 1.7 Hz, 1H), 8.03 (dd, J=8.6,1.7 Hz, 1H), 7.85-7.73 (m, 2H), 7.65 (dd, J=12.8, 7.7 Hz, 2H), 7.51-7.48(m, 1H), 7.35 (dd, J=8.4, 5.2 Hz, 1H), 7.20-7.12 (m, 1H), 5.54-5.37 (m,1H), 4.36 (dt, J=33.2, 6.8 Hz, 2H), 4.19-4.12 (m, 2H), 3.41-3.29 (m,2H), 2.71-2.61 (m, 1H), 2.54-2.41 (m, 1H), 2.34-2.19 (ms, 2H), 1.72-1.36(m, 24H). ¹⁹F NMR (376 MHz, CDCl₃) δ −59.38, −59.42, −59.44, −59.47,−59.48, −59.64, −59.71, −60.28.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(2-oxo-2-phenylethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate6p (6z)

6z was synthesized using general procedure 5 and isolated as a clearresidue (3 mg, 8%). 1H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J=1.6 Hz,1H), 8.09-8.00 (m, 3H), 7.85 (d, J=9.0 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H),7.65-7.61 (m, 1H), 7.56-7.48 (m, 2H), 7.30 (dd, J=9.0, 2.5 Hz, 1H), 7.13(d, J=2.6 Hz, 1H), 5.61 (dd, J=7.8, 4.5 Hz, 1H), 5.41 (s, 2H), 3.96-3.85(m, 1H), 3.86-3.73 (m, 1H), 2.51-2.37 (m, 1H), 2.27-2.16 (m, 2H),2.02-1.97 (m, 2H), 1.68-1.33 (m, 32H). HRMS (ESI+): Calcd for C₃₅H₃₉N₅O₇[M+H]⁺: 642.7214, Found: 642.2962.

Tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(6-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate(6aa)

6aa was synthesized using general procedure 5 and isolated as a clearresidue (4 mg, 10%). ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J=1.6 Hz, 1H),8.15 (dt, J=8.0, 0.9 Hz, 2H), 8.08 (dd, J=8.6, 1.7 Hz, 1H), 7.86 (d,J=9.0 Hz, 1H), 7.81-7.74 (m, 3H), 7.28 (dd, J=9.0, 2.6 Hz, 1H), 7.13 (d,J=2.6 Hz, 1H), 5.61 (dd, J=7.9, 4.6 Hz, 1H), 5.38 (s, 2H), 3.93-3.88 (m,1H), 3.84-3.73 (m, 1H), 2.49-2.39 (m, 1H), 2.28-2.17 (m, 2H), 2.02-1.96(m, 2H), 1.57-1.33 (m, 33H). HRMS (ESI+): Calcd for C₃₆H₃₈F₃N₅O₇[M+H]⁺710.7194, Found: 710.2802.

Tert-butyl(S,Z)-((2-(3-(6-(2-([1,1′-biphenyl]-4-yl)-2-oxoethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate(6bb)

6bb was synthesized using general procedure 5 and isolated as a clearresidue (6 mg, 15%). ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=1.6 Hz, 1H),8.14-8.10 (m, 1H), 8.07 (dd, J=8.6, 1.7 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H),7.79-7.71 (m, 2H), 7.65-7.60 (m, 2H), 7.51-7.45 (m, 2H), 7.42 (d, J=7.2Hz, 1H), 7.32 (dd, J=9.0, 2.6 Hz, 1H), 7.16 (d, J=2.6 Hz, 1H), 5.74-5.64(m, 1H), 5.43 (s, 2H), 3.98-3.88 (m, 1H), 3.88-3.79 (m, 1H), 2.51-2.39(m, 1H), 2.32-2.16 (m, 2H), 2.10-2.00 (m, 1H), 1.67-1.32 (m, 21H). HRMS(ESI+): Calcd for C₄₁H₄₃N₅O₇ [M+H]⁺: 718.8174, Found: 718.3275.

Example 68:(S)-amino(2-(3-(6-(3-methoxypropoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7k, compound 57A)

7k was synthesized using general procedure 3 and isolated as a whitesolid (1 mg, 47%). MS (ESI+): Calcd for C₂₁H₂₅N₅O₃ [M+H]⁺: 395.4628,Found: 396.72.

Example 69:(S)-amino(2-(3-(6-(4-methoxybutoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7l, compound 65A)

7l was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 91%). ¹H NMR (400 MHz, CD₃OD) δ 8.53-8.48 (m, 1H),8.07-7.99 (m, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.47 (s, 1H), 7.33-7.29 (m,1H), 7.24-7.16 (m, 1H), 5.46 (dd, J=7.7, 2.1 Hz, 1H), 4.16 (t, J=6.3 Hz,2H), 3.85-3.77 (m, 1H), 3.77-3.70 (m, 1H), 3.52-3.45 (m, 2H), 3.36 (s,3H), 2.61-2.45 (m, 2H), 2.29-2.22 (m, 1H), 2.17-2.09 (m, 1H), 1.96-1.89(m, 1H), 1.83-1.76 (m, 1H). MS (ESI+): Calcd for C₂₂H₂₇N₅O₃ [M+H]⁺:410.4894, Found: 410.46.

Example 70:(S)-amino(2-(3-(6-(cyclopentylmethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7m, compound 66A)

7m was synthesized using general procedure 3 and isolated as a whitesolid (1 mg, 69%). MS (ESI+): Calcd for C₂₃H₂₇N₅O₂ [M+H]⁺: 406.5007,Found: 406.24.

Example 71:(S)-amino(2-(3-(6-((4-(trifluoromethyl)benzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7n, compound 52A)

7n was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 66%). ¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 8.05 (dd,J=8.6, 1.8 Hz, 1H), 7.92 (dd, J=16.1, 8.8 Hz, 2H), 7.72 (s, 2H), 7.48(s, 1H), 7.43 (d, J=2.5 Hz, 1H), 7.35 (dd, J=9.0, 2.5 Hz, 1H), 5.47 (dd,J=7.8, 2.0 Hz, 1H), 5.36 (s, 2H), 3.84-3.77 (m, 1H), 3.67-3.62 (m, 1H),2.61-2.52 (m, 2H), 2.29-2.22 (m, 1H), 2.14 (t, J=9.6 Hz, 1H), 2.03 (d,J=7.8 Hz, 1H). MS (ESI+): Calcd for C₂₅H₂₂F₃N₅O₂ [M+H]⁺: 482.4776,Found: 482.43.

Example 72:(S)-amino(2-(3-(6-((3-(trifluoromethyl)benzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7o, compound 67A)

7o was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 66%). ¹H NMR (400 MHz, CD_(k)OD) δ 8.46-8.43 (m, 1H),7.98-7.91 (m, 2H), 7.86-7.78 (m, 2H), 7.76 (d, J=8.7 Hz, 1H), 7.70 (s,1H), 7.64 (d, J=7.7 Hz, 1H), 7.45 (s, 1H), 7.17-7.13 (m, 1H), 5.21 (t,J=8.4 Hz, 1H), 4.64 (d, J=13.1 Hz, 2H), 3.79-3.68 (m, 2H), 2.87-2.77 (m,1H), 2.49-2.32 (m, 2H), 2.30-2.19 (m, 1H). MS (ESI+): Calcd forC₂₅H₂₂F₃N₅O₂ [M+H]⁺: 482.4776, Found: 482.43.

Example 73:(S)-amino(2-(3-(6-((4-bromobenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7p, compound 53A)

7p was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 87%). MS (ESI+): Calcd for C₂₄H₂₂BrN₅O₂ [M+H]⁺: 493.3757,Found: 493.19.

Example 74:(S)-amino(2-(3-(6-((3-bromobenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7q, compound 58A)

7q was synthesized using general procedure 3 and isolated as a whitesolid (1 mg, 66%). MS (ESI+): Calcd for C₂₄H₂₂BrN₅O₂ [M+H]⁺: 493.3757,Found: 493.18.

Example 75:(S)-amino(2-(3-(6-((4-chlorobenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7r, compound 69A)

7r was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 67%). ¹H NMR (400 MHz, CD₃OD) δ 8.53-8.44 (m, 1H), 7.98(dd, J=8.6, 1.7 Hz, 1H), 7.94-7.85 (m, 1H), 7.79 (d, J=8.6 Hz, 1H),7.61-7.52 (m, 2H), 7.52-7.41 (m, 2H), 7.24-7.14 (m, 2H), 5.24 (t, J=8.5Hz, 1H), 4.60 (d, J=13.0 Hz, 2H), 3.76-3.73 (m, 1H), 3.60-3.56 (m, 1H),2.90-2.80 (m, 1H), 2.54-2.45 (m, 1H), 2.45-2.35 (m, 1H), 2.33-2.21 (m,1H). MS (ESI+): Calcd for C₂₄H₂₂ClN₅O₂ [M+H]⁺: 448.9247, Found: 448.92.

Example 76:(S)-amino(2-(3-(6-((3-chlorobenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7s, compound 68A)

7s was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 89%). ¹H NMR (400 MHz, CD₃OD) δ 8.51-8.46 (m, 1H), 7.98(dd, J=8.6, 1.7 Hz, 1H), 7.90-7.85 (m, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.68(q, J=1.4 Hz, 1H), 7.52-7.46 (m, 1H), 7.46-7.41 (m, 2H), 7.21-7.15 (m,2H), 5.27 (t, J=8.4 Hz, 1H), 4.61 (d, J=13.0 Hz, 1H), 3.84-3.76 (m, 1H),3.62-3.55 (m, 1H), 291-2.78 (m, 1H), 2.57-2.38 (m, 2H), 2.33-2.23 (m,1H). MS (ESI+): Calcd for C₂₄H₂₂ClN₅O₂ [M+H]⁺: 448.9247, Found: 448.92.

Example 77:(S)-amino(2-(3-(6-((4-cyanobenzyl)oxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7t, compound 70A)

7t was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 67%). HRMS (ESI+): Calcd for C₃₂H₃₇N₆O₂ [M+H]⁺: 439.4891,Found: 439.36.

Example 78:(S)-amino(2-(3-(6-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7u, compound 71A)

7u was synthesized using general procedure 3 and isolated as a whitesolid (3 mg, 93%). ¹H NMR (400 MHz, CD₃OD) δ 8.44 (d, J=1.6 Hz, 1H),7.93 (d, J=9.4 Hz, 1H), 7.84 (d, J=9.5 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H),7.47 (d, J=1.5 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.25 (dd, J=8.1, 1.9 Hz,1H), 7.20-7.16 (m, 2H), 5.21 (t, J=8.2 Hz, 1H), 4.60 (s, 2H), 3.92-3.82(m, 2H), 2.86-2.77 (m, 1H), 2.44-2.26 (s, 3H), 1.58 (d, J=9.1 Hz, 4H),1.31-1.28 (m, 3H), 1.23 (s, 3H), 1.11 (s, 3H), 1.04 (s, 3H). MS (ESI+):Calcd for C₃₂H₃₇N₅O₂ [M+H]⁺: 524.6764, Found: 524.68.

Example 79:(S)-(2-(3-(6-([1,1′-biphenyl]-4-ylmethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(amino)methaniminiumchloride (7v, compound 72A)

7v was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 87%). ¹H NMR (400 MHz, CD₃OD) δ 8.60-8.52 (m, 2H),8.35-8.31 (m, 1H), 8.20 (dd, J=9.0, 1.7 Hz, 1H), 8.04 (d, J=1.7 Hz, 1H),8.02-7.97 (m, 1H), 7.90 (d, J=9.3 Hz, 1H), 7.68-7.59 (m, 4H), 7.47-7.42(m, 2H), 7.36-7.31 (m, 2H), 5.47 (d, J=7.9 Hz, 1H), 5.44 (s, 1H), 5.31(s, 1H), 3.77-3.73 (m, 2H), 2.60-2.51 (m, 2H), 2.29-2.23 (m, 1H),2.16-2.10 (m, 1H). MS (ESI+): Calcd for C₃₀H₂₇N₅O₂ [M+H]⁺: 490.5756,Found: 490.36.

Example 80:(S)-amino(2-(3-(6-(4-(trifluoromethyl)phenethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7w, compound 54A)

7w was synthesized using general procedure 3 and isolated as a whitesolid (3 mg, 98%). ¹⁹F NMR (376 MHz, CD₃OC) δ −63.94. MS (ESI+): Calcdfor C₂₆H₂₄F₃N₅O₂ [M+H]⁺: 496.5042, Found: 496.27.

Example 81:(S)-amino(2-(3-(6-(3-(trifluoromethyl)phenethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7x, compound 60A)

7x was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 87%) HRMS (ESI+): Calcd for C₂₆H₂₄F₃N₅O₂ [M+H]⁺: 496.5042,Found: 496.27.

Example 82:(S)-amino(2-(3-(6-(2-(trifluoromethyl)phenethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7y, compound 55A)

7y was synthesized using general procedure 3 and isolated as a whitesolid (1 mg, 65%). HRMS (ESI+): Calcd for C₂₆H₂₄F₃N₅O₂ [M+H]⁺: 496.5042,Found: 496.27.

(S)-amino(2-(3-(6-(2-oxo-2-phenylethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7z)

7z was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 90%). ¹H NMR (400 MHz, CD₃OD) δ 8.54 (d, J=1.6 Hz, 1H),8.11 (dd, J=8.5, 1.3 Hz, 1H), 8.04 (dd, J=8.6, 1.7 Hz, 1H), 7.94 (d,J=8.9 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.72-7.67 (m, 1H), 7.58 (dd,J=8.3, 7.1 Hz, 2H), 7.47 (s, 1H), 7.38-7.34 (m, 1H), 5.64 (s, 2H), 5.46(dd, J=7.8, 2.1 Hz, 1H), 3.84-3.77 (m, 1H), 3.76-3.72 (m, 1H), 2.59-2.49(m, 2H), 2.28-2.22 (m, 1H), 2.16-2.10 (m, 1H). MS (ESI+): Calcd forC₂₅H₂₃N₅O₃ [M+H]⁺: 442.4898, Found: 442.44.

(S)-amino(2-(3-(6-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7aa)

7aa was synthesized using general procedure 3 and isolated as a whitesolid (2 mg, 65%). ¹H NMR (400 MHz, CD₃OD) δ 8.54 (d, J=1.8 Hz, 1H),8.28 (d, J=8.1 Hz, 2H), 8.05 (dd, J=8.6, 1.7 Hz, 1H), 7.94 (d, J=8.5 Hz,1H), 7.90-7.83 (m, 2H), 7.50-7.44 (m, 3H), 7.39-7.35 (m, 1H), 5.67 (s,2H), 5.47-5.44 (m, 1H), 2.58-2.45 (m, 2H), 2.16-2.11 (m, 1H), 2.06-2.01(m, 1H). MS (ESI+): Calcd for C₂₆H₂₂F₃N₅O₃ [M+H]⁺: 510.4877, Found:510.44.

(S)-(2-(3-(6-(2-([1,1′-biphenyl]-4-yl)-2-oxoethoxy)naphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(amino)methaniminiumchloride (7bb)

7bb was synthesized using general procedure 3 and isolated as a whitesolid (6 mg, 66%). ¹H NMR (400 MHz, CD₃OD) δ 8.54 (d, J=1.7 Hz, 1H),8.23-8.17 (m, 1H), 8.05 (dd, J=8.6, 1.7 Hz, 1H), 7.92 (dd, J=23.2, 9.2Hz, 2H), 7.87-7.80 (m, 1H), 7.75-7.69 (m, 1H), 7.52-7.34 (m, 5H), 5.67(s, 1H), 5.46 (dd, J=7.8, 2.0 Hz, 1H), 3.83-3.77 (m, 1H), 3.76-3.72 (m,1H), 2.65-2.48 (m, 2H), 2.28-2.20 (m, 1H), 2.15-2.07 (m, 1H). MS (ESI+):Calcd for C₃₁H₂₇F₃N₅O₃ [M+H]⁺: 518.5857, Found: 518.48.

Example 83:(S)-amino(2-(3-(6-hydroxynaphthalen-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminiumchloride (7cc, compound 51)

7cc was synthesized using general procedure 3 and isolated as a whitesolid (7 mg, 93%). ¹H NMR (400 MHz, Methanol-d₄) δ 8.47 (d, J=1.6 Hz,1H), 7.98 (dd, J=8.6, 1.7 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.76 (d,J=8.6 Hz, 1H), 7.16 (d, J=8.5 Hz, 2H), 5.47 (d, J=7.1 Hz, 1H), 3.85-3.76(m, 1H), 3.66 (s, 1H), 2.64-2.54 (m, 2H), 2.30-2.20 (m, 1H), 2.18-2.04(m, 1H). HRMS (ESI+): Calcd for C₁₇H₁₇N₅O₂ [M+H]⁺: 324.3571, Found:324.49.

Examples 84-93 Synthesis and Characterization of Formulae IA and IBCompounds

Schemes 14(A) through 14(D) below outline general and specific syntheticmethodologies for the preparation of Compound Nos. 77A-96A. Compoundnumbering in the Schemes are internal to the Schemes, while thesubsequent procedures refer where applicable to the final compounds.

General Procedures I. General Procedure for Nucleophilic AromaticSubstitution

To a solution of (1) in THF was added potassium tertiary butoxide (1M inTHF) under cooling. The resultant solution was maintained at 75° C. for7-10 h. Cooled the reaction mixture to rt and partitioned betweenethylacetate and water. Extracted the aqueous layer twice withethylacetate. Combined organic layers were given water, brine washes.Dried over anhydrous Na₂SO₄ and purified on a silica column with hexaneand ethyl acetate.

II. General Procedure for Synthesis of Amidoxime

Nitrile intermediate (1 equiv.), hydroxylamine hydrochloride (3 equiv.),TEA (3 equiv.) were added to a round bottom flask containing ethanol.The reaction mixture was heated to 80° C. for 6-12 hours and monitoredvia TLC. Once the starting material was consumed, the solution wascooled to room temperature, concentrated under reduced pressure, loadedonto celite, and purified on a silica column with hexane and ethylacetate.

III. General Procedure for Synthesis of 1,2,4-Oxadiazole

Amidoxime intermediate (1 equiv.), Boc-L-proline (1.4 equiv.) orBoc-trans-3-hydroxy-L-proline (1.4 equiv.), and DIEA (1.4 equiv.) wereadded to a round bottom flask containing DMF. HCTU (1.8 equiv.) wasadded to the reaction mixture and maintained at 110° C. for 12-16 hours.Cooled the reaction mixture to r.t. and partitioned between ethylacetate and saturated LiBr solution. The combined organic layers werewashed with sat. NaHCO₃, brine and dried over sodium sulfate. Combinedorganic layers were subjected to rotary evaporation and columnchromatography to afford the desired Oxadiazole intermediate.

IV. General Procedure for O-Alkylation

(1 equiv.), potassium carbonate (2 equiv.), KI (1.5 equiv.) and alkylhalide (1.2 equiv.) were added to a 8 mL microwave reactor containingacetone. The reaction mixture was heated to 80° C. for 4-12 hours untilTLC indicated the starting material had been fully consumed. Thereaction mixture was extracted with ethyl acetate and D.I. water. Thecombined organic layers were washed with brine and dried over sodiumsulfate. After filtration and concentration via reduced pressure, theresulting brown oil was purified on a silica column with hexane andethyl acetate.

V. General Procedure for Boc-Deprotection

N-Boc Pyrrolidine or N′, N″-Di-Boc-guanidine 6a-e was dissolved inmethanol. HCl gas was bubbled into the solution for 1 minute. Thesolution was stirred until TLC indicated that all of the Boc-protectedamine had been consumed. The solvent was removed under reduced pressure.The resulting white to light yellow solid was washed with diethyl etherto yield pure product as HCl salt.

VI. General Procedure for Guanylation of Secondary Amines

Pyrrolidine Hydrogen chloride salt (1 equiv.) was added to a 8 mLmicrowave reaction flash with acetonitrile and DIEA (3 equiv.). Thesolution was allowed to stir for 10 minutes before the addition of(Z)-Tert-butyl(((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (1.05equiv.). The solution was subjected to microwave irradiation at 55° C.for 2-6 h until TLC indicated that the starting material had beenconsumed. The reaction mixture is subjected to rotary evaporation andperformed column chromatography to afford the N′,N′-diboc guanidineintermediate.

VII. General Procedure for Mitsunobu Reaction

To a pre-cooled solution of 23 in dry THF and PPh₃ added DIAD (40% intoluene) and alcohol. The reaction mixture was stirred for 1 h thenrefluxed for 2 h. Quenched reaction mixture with aqueous NaHCO₃, rotaryevaporated and partitioned between dichloromethane and DI water.Combined organic layers were subjected to rotatory evaporation andperformed column chromatography to afford the desired product.

VIII. General Procedure for Cross Metathesis Using Microwave Synthesizer

Dissolved the O-Allyl intermediate (6) in dry DCM. Added terminal alkene(excess) followed by Grubbs's II generation catalyst (10 mol %) at rt ina microwave reaction capsule. Subjected to microwave irradiation 70° C.,300 power, 2-4 h. Rotary evaporated the crude, performed columnchromatography to afford the desired product.

IX. General Procedure for Cross Metathesis Using Bench Top

Dissolved the O-Allyl intermediate (6) in dry DCM. Added terminal alkene(excess) followed by Grubbs's II generation catalyst (4×4 mol %).Subjected to vigorous reflux for 2-3 days Rotary evaporated the crude,performed column chromatography to afford the desired product.

4-(tert-butoxy)-3-(trifluoromethyl)benzonitrile (2)

¹H NMR (500 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.73 (dd, J=8.8, 2.1 Hz,1H), 7.27 (d, J=8.7 Hz, 1H), 1.56 (s, 9H).

(Z)-4-(tert-butoxy)-N′-hydroxy-3-(trifluoromethyl)benzimidamide (3)

¹H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J=2.3 Hz, 1H), 7.72 (dd,J=8.7, 2.4 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 6.72 (s, 1H), 4.84 (s, 2H),1.52 (s, 9H).

tert-butyl(S)-2-(3-(4-(tert-butoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(4)

¹H NMR (500 MHz, Chloroform-d) δ 8.21 (d, J=2.1 Hz, 1H), 8.05 (dd,J=8.6, 2.2 Hz, 1H), 7.20 (t, J=8.6 Hz, 1H), 5.15-5.05 (m, 0.4H),5.04-4.95 (m, 0.6H), 3.71-3.55 (m, 1H), 3.53-3.31 (m, 1H), 2.31-2.21 (m,1H), 2.15-2.05 (m, 2H), 1.99-1.83 (m, 1H), 1.39 (s, 3H), 1.24 (s, 6H).

tert-butyl(S)-2-(3-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate(5)

¹H NMR (400 MHz, Methanol-d₄) δ 8.16 (d, J=2.1 Hz, 1H), 8.10-8.04 (m,1H), 7.07 (d, J=8.7 Hz, 1H), 5.16-5.08 (m, 1H), 3.70-3.61 (m, 1H),3.55-3.48 (m, 1H), 2.53-2.36 (m, 1H), 2.20-2.00 (m, 3H), 1.46 (s, 3H),1.27 (s, 6H); ¹³C NMR (101 MHz, Methanol-d₄) δ 181.0, 167.2, 154.0,131.9, 125.8, 124.9, 117.2, 117.0, 80.5, 53.8, 46.1, 31.8, 31.0, 27.2,26.9, 23.9, 23.3.

tert-butyl(S)-2-(3-(4-(allyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J=2.1 Hz, 1H), 8.17 (d, J=8.7Hz, 1H), 7.05 (t, J=8.5 Hz, 1H), 6.03 (ddt, J=17.3, 10.7, 4.8 Hz, 1H),5.57-5.39 (m, 1H), 5.32 (d, J=10.6 Hz, 1H), 5.04 (dd, J=8.3, 3.6 Hz,1H), 4.69 (d, J=4.7 Hz, 2H), 3.70 (s, 1H), 3.64-3.40 (m, 1H), 2.49-2.26(m, 1H), 2.19-1.91 (m, 3H), 1.45 (s, 3H), 1.28 (s, 5H); ¹³C NMR (126MHz, CDCl₃) δ 180.9, 180.4, 167.2, 158.6, 154.3, 153.5, 132.4, 131.7,126.7, 124.3, 122.1, 119.2, 119.0, 113.4, 80.5, 69.3, 53.8, 46.4, 32.4,31.5, 28.1, 24.4, 23.7.

tert-butyl(S)-2-(3-(4-(but-3-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J=2.2 Hz, 1H), 8.17 (dd,J=8.6, 2.4 Hz, 1H), 7.04 (t, J=9.0 Hz, 1H), 5.95-5.83 (m, 1H), 5.22-5.01(m, 3H), 4.13 (t, J=6.4 Hz, 2H), 3.76-3.41 (m, 2H), 2.58 (qt, J=6.7, 1.3Hz, 2H), 2.47-2.26 (m, 1H), 2.21-2.01 (m, 2H), 2.06-1.90 (m, 2H), 1.44(s, 3H), 1.22 (s, 6H); ¹³C NMR (101 MHz, cdcl₃) δ 180.8, 167.2, 158.9,153.5, 133.6, 132.4, 126.5, 126.5, 118.7, 117.5, 112.9, 112.8, 80.4,68.3, 53.7, 46.6, 46.3, 33.3, 32.4, 31.4, 28.3, 28.1, 24.3, 23.7.

tert-butyl(S)-2-(3-(4-(hex-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J=2.1 Hz, 1H), 8.15 (dd,J=8.8, 2.3 Hz, 1H), 7.05 (t, J=8.7 Hz, 1H), 5.85 (dt, J=15.4, 6.8 Hz,1H), 5.72-5.58 (m, 1H), 5.04 (dd, J=8.1, 3.6 Hz, 1H), 4.63 (d, J=5.7 Hz,2H), 3.74-3.61 (m, 1H), 3.60-3.41 (m, 1H), 2.36 (s, 1H), 2.19-1.91 (m,6H), 1.50-1.35 (m, 5H), 0.89 (q, J=7.7 Hz, 3H).

tert-butyl(S)-2-(3-(4-(hept-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J=2.1 Hz, 1H), 8.16 (dd,J=8.8, 2.3 Hz, 1H), 7.05 (t, J=8.6 Hz, 1H), 5.86 (dt, J=14.2, 6.8 Hz,1H), 5.72-5.58 (m, 1H), 5.04 (dd, J=7.9, 3.6 Hz, 1H), 4.71-4.52 (m, 2H),3.75-3.65 (m, 1H), 3.54-3.48 (m, 1H), 2.21-1.92 (m, 5H), 1.49-1.17 (m,12H), 0.95-0.82 (m, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ 187.5, 163.3,132.1, 132.1, 128.4, 119.5, 119.5, 109.6, 109.6, 73.4, 73.0, 72.7, 65.7,65.7, 51.3, 45.5, 45.5, 28.0, 27.1, 27.1, 25.7, 25.7, 24.1, 24.1, 18.2,18.2, 9.9.

tert-butyl(S)-2-(3-(4-(oct-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (500 MHz, Chloroform-d) δ 8.22 (d, J=2.2 Hz, 1H), 8.11 (qd,J=5.8, 3.7, 3.3 Hz, 1H), 7.00 (dd, J=11.0, 8.2 Hz, 1H), 5.81 (dt,J=15.7, 6.8 Hz, 1H), 5.64-5.53 (m, 1H), 5.14-5.05 (m, 0H), 4.99 (dd,J=8.3, 3.7 Hz, 1H), 4.58 (d, J=5.4 Hz, 2H), 3.71-3.38 (m, 2H), 2.33(dtd, J=18.9, 10.3, 8.3, 5.3 Hz, 1H), 2.14-1.86 (m, 5H), 1.40-1.07 (m,13H), 0.92-0.71 (m, 3H).

tert-butyl(S,E)-2-(3-(4-(hept-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 8.16 (s, 1H), 7.06 (d,J=8.7 Hz, 1H), 5.85 (d, J=7.1 Hz, 1H), 5.64 (d, J=15.5 Hz, 1H), 5.16 (s,0H), 5.02 (s, 1H), 4.62 (s, 2H), 3.69 (s, 1H), 3.56 (s, 1H), 2.39 (s,1H), 2.21-1.92 (m, 5H), 1.44 (s, 3H), 1.41-1.22 (m, 9H), 0.89 (s, 3H).

tert-butyl(S,E)-2-(3-(4-(oct-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J=2.1 Hz, 1H), 8.15 (dd,J=8.7, 2.3 Hz, 1H), 7.05 (t, J=8.8 Hz, 1H), 5.85 (dtt, J=15.0, 6.8, 1.4Hz, 1H), 5.64 (dtt, J=15.4, 5.7, 1.4 Hz, 1H), 4.63 (d, J=5.4 Hz, 2H),3.74-3.59 (m, 1H), 3.59-3.42 (m, 1H), 2.47-2.28 (m, 1H), 2.22-1.94 (m,6H), 1.49-1.14 (m, 16H), 0.90-0.79 (m, 3H); ¹³C NMR (101 MHz, cdcl₃) δ180.8, 167.2, 158.8, 153.5, 136.1, 132.2, 123.4, 113.6, 113.4, 80.4,69.6, 53.7, 46.6, 46.3, 32.4, 32.2, 31.4, 31.3, 28.5, 28.3, 28.1, 24.3,23.7, 22.4, 14.0.

tert-butyl(S,Z)-2-(3-(4-(hept-3-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J=2.1 Hz, 1H), 8.17 (dd,J=8.7, 2.3 Hz, 1H), 7.04 (t, J=8.7 Hz, 1H), 5.60-5.40 (m, 2H), 4.09 (t,J=6.8 Hz, 2H), 3.68 (dd, J=12.2, 6.6 Hz, 1H), 3.52 (ddd, J=28.5, 15.2,8.0 Hz, 1H), 2.59 (q, J=6.9 Hz, 2H), 2.38 (td, J=11.1, 10.3, 5.3 Hz,1H), 2.19-1.90 (m, 6H), 1.49-1.20 (m, 12H), 0.90 (t, J=7.4 Hz, 3H); ¹³CNMR (101 MHz, cdcl₃) δ 180.8, 167.2, 132.9, 132.3, 126.6, 124.0, 112.9,112.8, 80.4, 68.7, 53.7 46.6, 46.3, 32.4, 31.4, 29.3, 28.3, 28.1, 27.1,24.3, 23.7, 22.7, 13.7.

tert-butyl(S,Z)-2-(3-(4-(oct-3-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 8.17 (d, J=8.7 Hz, 1H),7.04 (t, J=8.5 Hz, 1H), 5.60-5.40 (m, 2H), 5.17 (d, J=7.9 Hz, 1H), 5.04(dd, J=8.1, 3.7 Hz, 1H), 4.09 (t, J=6.8 Hz, 2H), 3.77-3.62 (m, 1H),3.62-3.40 (m, 1H), 2.59 (q, J=6.9 Hz, 2H), 2.48-2.29 (m, 1H), 2.26-1.91(m, 6H), 1.45 (s, 3H), 1.40-1.18 (m, 10H), 0.94-0.79 (m, 3H); ¹³C NMR(101 MHz, cdcl₃) δ 180.8, 167.2, 159.0, 153.5, 133.1, 132.3, 126.7,126.6, 126.5, 123.8, 118.6, 112.9, 112.8, 80.4, 68.7, 53.7, 46.6, 46.3,32.4, 31.7, 31.4, 28.3, 28.1, 27.1, 27.0, 24.3, 23.7, 22.3, 13.9.

tert-butyl(S,E)-2-(3-(4-((3-(4-fluorophenyl)allyl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.30 (s, 1H), 8.19 (d, J=8.8 Hz, 1H),7.40-7.32 (m, 2H), 7.15-7.07 (m, 1H), 7.04-6.95 (m, 2H), 6.74 (d, J=16.1Hz, 1H), 6.33-6.22 (m, 1H), 5.17 (d, J=8.1 Hz, 1H), 5.04 (dd, J=8.3, 3.6Hz, 1H), 4.85 (d, J=5.4 Hz, 2H), 3.69 (s, 1H), 3.61-3.38 (m, 2H), 2.39(s, 1H), 2.22-1.89 (m, 3H), 1.45 (s, 3H), 1.28 (s, 6H); ¹³C NMR (101MHz, cdcl₃) δ 191.4, 180.9, 167.2, 132.4, 132.1, 128.2, 128.1, 126.7,122.6, 119.1, 115.7, 115.4, 113.4, 113.3, 80.5, 69.3, 53.7, 46.6, 46.3,32.4, 31.4, 28.3, 28.1, 24.3, 23.7.

tert-butyl(S,E)-2-(3-(4-((3-(3-bromophenyl)allyl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 1H), 8.23 (d, J=8.7 Hz, 1H), 7.58(t, J=1.8 Hz, 1H), 7.42 (ddd, J=7.9, 2.0, 1.0 Hz, 1H), 7.37-7.33 (m,1H), 7.23 (t, J=7.8 Hz, 1H), 7.14 (t, J=8.9 Hz, 1H), 6.75 (d, J=16.0 Hz,1H), 6.41 (dt, J=16.0, 5.2 Hz, 1H), 5.08 (dd, J=8.1, 3.6 Hz, 1H), 4.90(d, J=5.1 Hz, 2H), 3.77-3.42 (m, 2H); ¹³C NMR (101 MHz, cdcl₃) δ 167.2,138.3, 132.4, 131.6, 130.1, 129.5, 126.8, 125.3, 124.5, 122.8, 113.4,110.0, 80.5, 69.0, 53.8, 46.3, 32.4, 29.7, 28.4, 28.1, 23.7.

((3-(3-(trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=2.1 Hz, 1H), 8.19 (dd,J=8.7, 2.3 Hz, 1H), 7.63 (dd, J=8.2, 1.3 Hz, 2H), 7.50 (td, J=7.7, 1.4Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.20 (dq, J=15.9, 2.1 Hz, 1H), 7.11 (t,J=8.8 Hz, 1H), 6.33 (dt, J=15.8, 5.1 Hz, 1H), 5.22-4.98 (m, 1H),3.76-3.63 (m, 1H), 3.58-3.31 (m, 1H), 2.48-2.21 (m, 1H), 2.21-2.05 (m,2H), 2.04-1.93 (m, 1H), 1.45 (s, 3H), 1.39-1.13 (m, 6H); ¹³C NMR (101MHz, cdcl₃) δ 180.8, 167.2, 158.8, 158.8, 153.5, 136.1, 132.2, 132.2,126.6, 126.6, 123.4, 118.6, 113.6, 113.4, 113.4, 110.0, 80.5, 80.5,69.6, 69.6, 53.7, 53.7, 46.6, 46.3, 46.3, 32.4, 31.9, 31.4, 31.0, 28.3,28.1, 24.3, 23.7, 22.1, 13.8.

tert-butyl(S,E)-2-(3-(3-(trifluoromethyl)-4-((3-(3-trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.33 (d, J=2.1 Hz, 1H), 8.24-8.18 (m,1H), 7.65 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.46(t, J=7.7 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 6.87-6.79 (m, 1H), 6.46 (dt,J=16.0, 5.1 Hz, 1H), 5.06 (dd, J=8.2, 3.6 Hz, 1H), 4.89 (d, J=5.1 Hz,2H), 3.77-3.44 (m, 2H), 2.51-2.28 (m, 1H), 2.21-2.15 (m, 2H), 2.08-1.91(m, 1H), 1.67-1.20 (m, 9H); ¹³C NMR (101 MHz, cdcl₃) δ 167.1, 136.9,132.4, 131.5, 129.8, 129.7, 129.1, 124.9, 124.6, 123.3, 123.2, 113.4,80.5, 68.9, 53.8, 46.6, 46.3, 32.4, 29.7, 28.3, 28.1, 24.4, 23.7;tert-butyl(S,E)-2-(3-(3-(trifluoromethyl)-4-((3-(4-(trifluoromethyl)phenyl)allyl)oxy)phenyl)1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (500 MHz, Chloroform-d) δ 8.29-8.22 (m, 1H), 8.19-8.10 (m, 1H),7.52 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.05 (dd, J=12.8, 8.6Hz, 1H), 6.77 (d, J=16.1 Hz, 1H), 6.42 (dt, J=16.1, 5.1 Hz, 1H), 5.13(d, J=7.8 Hz, 0H), 4.99 (dd, J=8.1, 3.7 Hz, 1H), 4.83 (dt, J=6.0, 2.8Hz, 1H), 3.64 (dd, J=14.6, 8.8 Hz, 1H), 3.55-3.36 (m, 1H), 2.43-2.21 (m,1H), 2.16-2.01 (m, 2H), 1.94 (s, 1H), 1.39 (s, 3H), 1.21 (s, 6H); ¹³CNMR (126 MHz, CDCl₃) δ 153.4, 146.4, 137.7, 127.6, 121.9, 120.7, 120.7,120.5, 108.4, 100.0, 72.7, 72.4, 72.3, 72.2, 72.1, 72.0, 72.0, 71.8,71.8, 71.7, 48.9, 23.2, 23.2.

tert-butyl(S,Z)-2-(3-(3-(trifluoromethyl)-4-((3-(4-trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (500 MHz, Chloroform-d) δ 8.24 (d, J=2.4 Hz, 1H), 8.08 (dd,J=8.6, 2.4 Hz, 1H), 7.58 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 6.87(t, J=9.3 Hz, 1H), 6.74 (d, J=11.9 Hz, 1H), 6.04 (dt, J=11.7, 6.4 Hz,1H), 4.99 (dd, J=8.1, 3.8 Hz, 1H), 4.91 (p, J=6.3 Hz, 1H), 4.87-4.81 (m,2H), 3.70-3.56 (m, 1H), 3.50 (dt, J=10.3, 7.1 Hz, 1H), 2.42-2.23 (m,1H), 2.15-2.01 (m, 2H), 2.00-1.90 (m, 1H), 1.39 (s, 3H), 1.29-1.13 (m,6H).

tert-butyl(S,E)-2-(3-(3-(trifluoromethyl)-4-((4-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J=2.2 Hz, 1H), 8.23-8.17 (m,1H), 7.55 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.08 (t, J=9.1 Hz,1H), 6.58 (d, J=15.9 Hz, 1H), 6.43 (dt, J=15.9, 6.9 Hz, 1H), 5.23-5.14(m, 1H), 5.06 (dd, J=8.2, 3.7 Hz, 1H), 4.24 (t, J=6.1 Hz, 2H), 3.77-3.44(m, 2H), 2.78 (q, J=6.4 Hz, 2H), 2.41 (ddd, J=19.3, 14.3, 9.7 Hz, 1H),2.15 (dtd, J=19.0, 10.2, 8.4, 5.2 Hz, 2H), 2.06-1.92 (m, 1H), 1.46 (s,3H), 1.29 (s, 6H); ¹³C NMR (101 MHz, cdcl₃) δ 180.9, 167.2, 167.2,158.8, 153.5, 140.7, 132.4, 131.6, 128.2, 126.8, 126.2, 125.5, 125.4,125.4, 122.8, 118.9, 118.9, 112.9, 80.5, 77.2, 77.0, 68.2, 53.8, 46.6,46.3, 32.6, 32.4, 31.5, 28.3, 28.1, 24.4, 23.7.

tert-butyl(S,E)-2-(3-(4-((3,7-dimethylocta-2,6-dien-1-yl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J=2.1 Hz, 1H), 8.17 (dd,J=8.7, 2.2 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 5.49-5.38 (m, 1H), 5.12-5.02(m, 2H), 4.71 (d, J=6.3 Hz, 2H), 4.15 (dq, J=6.9, 0.7 Hz, 1H), 3.78-3.61(m, 1H), 3.60-3.43 (m, 1H), 2.49-2.28 (m, 2H), 2.25-1.91 (m, 9H), 1.74(d, J=1.3 Hz, 3H), 1.69-1.62 (m, 3H), 1.46 (s, 3H), 1.29 (s, 6H); ¹³CNMR (101 MHz, cdcl₃) δ 191.3, 180.8, 180.3, 167.3, 159.0, 153.5, 150.9,150.8, 142.1, 142.0, 139.7, 132.2, 131.9, 131.7, 131.2, 126.6, 124.6,123.9, 123.5, 123.3, 121.8, 118.7, 118.5, 113.5, 80.5, 66.0, 59.4, 53.8,46.6, 46.3, 39.5, 39.4, 32.4, 31.4, 28.4, 28.1, 26.4, 26.1, 25.7, 25.6,24.4, 23.7, 22.4, 22.0, 21.7, 17.7, 17.4, 16.7, 16.3, 16.2; Calcd forC₂₈H₃₆F₃N₃O₄Na [M+Na]: 560.2611, Found: 560.2640.

tert-butyl(S,E)-((2-(3-(4-(allyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate

¹H NMR (500 MHz, Chloroform-d) δ 8.31 (d, J=2.1 Hz, 1H), 8.20 (dd,J=8.7, 2.2 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 6.11-5.98 (m, 1H), 5.62 (dd,J=7.8, 4.6 Hz, 1H), 5.50 (dq, J=17.3, 1.7 Hz, 1H), 5.35 (dq, J=10.7, 1.5Hz, 1H), 4.72 (dt, J=4.9, 1.7 Hz, 2H), 3.92 (dt, J=11.6, 6.8 Hz, 1H), s3.82 (ddd, J=11.4, 7.3, 5.7 Hz, 1H), 2.51-2.40 (m, 1H), 2.28-2.15 (m,2H), 2.10-2.00 (m, 1H), 1.47 (s, 18H); ¹³C NMR (126 MHz, CDCl₃) δ 179.2,167.2, 167.2, 158.5, 153.6, 132.4, 131.7, 126.9, 126.8, 119.0, 117.9,113.3, 81.0, 77.2, 69.3, 55.3, 49.5, 31.4, 28.1, 28.0, 24.0.

tert-butyl(S,Z)-((2-(3-(4-(but-3-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J=2.1 Hz, 1H), 8.16 (dd,J=8.7, 2.2 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 5.90 (ddt, J=17.1, 10.2, 6.8Hz, 1H), 5.61 (dd, J=7.9, 4.5 Hz, 1H), 5.20-5.06 (m, 2H), 4.14 (t, J=6.5Hz, 2H), 3.89 (dt, J=13.0, 6.8 Hz, 1H), 3.78 (dt, J=10.6, 5.9 Hz, 1H),2.51-2.38 (m, 2H), 2.44 (dq, J=16.0, 8.9, 7.9 Hz, 1H), 2.11-1.99 (m,2H), 2.09-1.95 (m, 2H), 1.45 (s, 18H); ¹³C NMR (101 MHz, cdcl₃) δ 179.1,167.2, 158.9, 153.5, 133.6, 132.5, 126.8, 126.7, 119.6, 119.3, 118.7,117.6, 112.8, 81.1, 68.3, 55.3, 49.6, 33.3, 31.4, 29.7, 28.1, 28.0,24.0.

tert-butyl((1E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(4-(hex-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 10.09 (s, 2H), 8.27 (d, J=2.1 Hz, 1H),8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 5.85 (dtt, J=15.0,6.7, 1.4 Hz, 1H), 5.71-5.51 (m, 2H), 4.63 (dd, J=5.6, 1.3 Hz, 2H),3.97-3.67 (m, 2H), 2.43 (dq, J=13.4, 7.8 Hz, 1H), 2.30-1.91 (m, 5H),1.57-1.33 (m, 17H), 1.33-1.12 (m, 6H), 0.98-0.74 (m, 6H).

tert-butyl((1E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(4-(hept-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹H NMR (500 MHz, Chloroform-d) δ 10.05 (s, 1H), 8.22 (d, J=2.1 Hz, 1H),8.10 (dd, J=8.7, 2.2 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 5.85-5.78 (m, 1H),5.67-5.49 (m, 2H), 4.59-4.53 (m, 2H), 3.88-3.65 (m, 2H), 2.46-2.30 (m,1H), 2.23-1.90 (m, 5H), 1.74-0.98 (m, 22H), 0.83 (t, J=7.2 Hz, 3H); ¹³CNMR (126 MHz, CDCl₃) δ 179.2, 167.2, 158.8, 158.8, 136.1, 132.3, 126.8,123.4, 118.7, 118.7, 113.5, 113.5, 100.0, 77.2, 69.6, 55.3, 49.5, 32.0,31.0, 29.7, 28.1, 22.1, 13.9.

tert-butyl((1E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(4-(oct-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹H NMR (500 MHz, Chloroform-d) δ 8.50-7.88 (m, 1H), 7.19 (s, 2H),6.03-5.25 (m, 2H), 4.79-4.19 (m, 1H), 4.01-3.58 (m, 1H), 2.38 (dd,J=13.4, 7.1 Hz, 1H), 2.26-1.82 (m, 3H), 1.54-0.52 (m, 24H); ¹³C NMR (101MHz, cdcl₃) δ 167.2, 167.2, 158.8, 136.1, 132.3, 132.3, 126.7, 123.4,113.5, 113.5, 77.2, 69.6, 69.6, 49.5, 49.5, 32.2, 32.2, 31.3, 31.3,29.7, 29.7, 28.5, 28.1, 28.0, 22.4, 14.0; ¹³C NMR (101 MHz, cdcl₃) δ176.9, 167.2, 166.6, 158.8, 158.4, 136.1, 132.3, 126.7, 123.4, 113.5,93.9, 69.6, 49.5, 42.3, 32.2, 28.0, 22.4, 14.0.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(4-(((E)-hept-2-en-1-yl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹H NMR (500 MHz, Chloroform-d) δ 10.02 (s, 1H), 8.22 (d, J=2.1 Hz, 1H),8.11 (dd, J=8.7, 2.2 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 5.81 (dtt, J=15.2,6.8, 1.4 Hz, 1H), 5.65-5.47 (m, 2H), 4.58 (dd, J=5.6, 1.4 Hz, 2H),3.88-3.64 (m, 2H), 2.39 (dt, J=13.6, 7.3 Hz, 1H), 2.20-1.90 (m, 6H),1.51-1.08 (m, 20H), 0.83 (t, J=7.2 Hz, 5H); ¹³C NMR (101 MHz,Methanol-d₄) δ 187.5, 163.3, 147.0, 132.1, 132.1, 128.4, 128.4, 127.9,119.5, 119.5, 115.9, 115.5, 114.8, 109.6, 109.6, 73.4, 73.0, 72.7, 65.7,65.7, 45.5, 45.5, 27.1, 25.7, 24.1, 18.2.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(4-(((E)-oct-2-en-1-yl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 10.09 (s, 2H), 8.27 (d, J=2.1 Hz, 1H),8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 5.86 (dtt, J=15.0,6.8, 1.4 Hz, 1H), 5.73-5.54 (m, 2H), 4.63 (dd, J=5.7, 1.3 Hz, 2H),4.01-3.57 (m, 3H), 2.29-1.95 (m, 5H), 1.73-1.10 (m, 26H), 1.03-0.71 (m,4H); ¹³C NMR (101 MHz, cdcl₃) δ 153.3, 136.1, 135.9, 132.3, 126.8,123.4, 113.5, 77.4, 77.1, 76.7, 76.4, 69.6, 57.5, 55.2, 49.4, 32.2,32.2, 31.3, 28.1, 22.4, 14.0.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(4-(((Z)-oct-3-en-1-yl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 10.08 (s, 2H), 8.28-8.25 (m, 1H),8.20-8.15 (m, 1H), 7.08-7.01 (m, 1H), 7.06 (d, J=8.8 Hz, 1H), 5.62-5.41(m, 3H), 4.10 (t, J=6.8 Hz, 2H), 3.93-3.84 (m, 1H), 3.84-3.72 (m, 1H),2.60 (qd, J=6.9, 1.3 Hz, 2H), 2.48-2.38 (m, 1H), 2.20-2.12 (m, 2H),2.18-1.81 (m, 3H), 1.45 (s, 18H), 1.37-1.29 (m, 4H), 0.93-0.86 (m, 3H);¹³C NMR (126 MHz, CDCl₃) δ 179.1, 167.2, 159.0, 133.1, 132.4, 126.8,126.8, 124.2, 123.9, 122.1, 119.6, 119.3, 118.7, 118.6, 112.9, 77.2,68.7, 55.3, 49.5, 31.7, 28.1, 27.1, 27.0, 22.3, 14.0.

tert-butyl((E)-((S)-2-(3-(4-(((E)-3-(3-bromophenyl)allyl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)((tert-butoxycarbonyl)amino)methylene)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 8.32 (d, J=2.1 Hz, 1H), 8.21 (dd,J=8.6, 2.2 Hz, 1H), 7.56 (t, J=1.8 Hz, 1H), 7.39 (dt, J=8.0, 1.4 Hz,1H), 7.35-7.30 (m, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H),6.78-6.68 (m, 1H), 6.70 (s, 1H), 6.39 (dt, J=16.0, 1H), 5.60 (dd, J=7.9,4.4 Hz, 1H), 4.87 (dd, J=5.2, 1.7 Hz, 2H), 3.90 (dt, J=13.2, 6.8 Hz,1H), 3.81 (s, 1H), 2.45 (dd, J=13.0, 7.1 Hz, 2H), 2.23-1.95 (m, 4H),1.48 (s, 18H); ¹³C NMR (126 MHz, CDCl₃) δ 179.3, 167.1, 158.4, 147.6,146.7, 138.3, 132.5, 131.6, 130.9, 130.1, 129.5, 125.3, 124.5, 122.8,113.3, 113.3, 77.6, 77.2, 69.0, 49.5, 29.7, 28.1, 28.0.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(4-(((E)-3-(4-fluorophenyl)allyl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

1H NMR (400 MHz, Chloroform-d) δ 10.51-9.51 (brs, 2H), 8.31 (d, J=2.1Hz, 1H), 8.20 (dd, J=8.7, 2.2 Hz, 1H), 7.42-7.34 (m, 2H), 7.12 (d, J=8.8Hz, 1H), 7.06-6.97 (m, 2H), 6.79-6.72 (m, 1H), 6.30 (dt, J=16.0, 5.4 Hz,1H), 5.63 (dd, J=7.7, 4.4 Hz, 1H), 4.86 (dd, J=5.5, 1.6 Hz, 2H),3.96-3.74 (m, 2H), 2.46 (s, 1H), 2.28-2.13 (m, 2H), 2.04 (dt, J=12.6,6.7 Hz, 1H), 1.48 (d, =20.4 Hz, 18H); ¹³C NMR (101 MHz, cdcl₃) δ 191.5,179.2, 179.2, 167.1, 163.8, 158.5, 132.5, 132.3, 132.3, 132.2, 128.2,128.2, 126.9, 126.9, 122.6, 122.6, 121.8, 119.6, 119.1, 115.7, 115.4,113.4, 77.2, 69.3, 55.3, 49.5, 36.6, 31.2, 28.1, 28.0, 24.7, 23.3.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(3-(trifluoromethyl)-4-(((E)-3-(2-(trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹³C NMR (101 MHz, cdcl₃) δ 191.5, 167.1, 167.1, 158.5, 151.2, 135.3,132.4, 131.9, 129.1, 127.7, 127.5, 127.2, 126.9, 125.8, 125.8, 124.5,113.4, 77.2, 68.9, 49.5, 29.7, 28.1, 28.0.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(3-(trifluoromethyl)-4-(((E)-3-(3-(trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹³C NMR (101 MHz, cdcl₃) δ 191.5, 179.3, 167.1, 158.3, 136.9, 132.5,132.1, 131.6, 130.9, 129.8, 129.1, 127.0, 126.9, 124.9, 124.6, 123.3,123.2, 123.2, 119.6, 119.3, 113.3, 77.2, 68.9, 55.3, 49.5, 29.7, 28.1,28.0.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(3-(trifluoromethyl)-4-(((E)-3-(4-(trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹H NMR (500 MHz, Chloroform-d) δ 10.09 (s, 1H), 8.26 (d, J=2.1 Hz, 1H),8.15 (dd, J=8.7, 2.1 Hz, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz,2H), 7.05 (d, J=8.7 Hz, 1H), 6.80-6.73 (m, 1H), 6.42 (dt, J=16.1, 5.1Hz, 1H), 5.54 (dd, J=7.9, 4.5 Hz, 1H), 4.83 (dd, J=5.1, 1.7 Hz, 2H),3.91-3.65 (m, 2H), 2.45-2.33 (m, 1H), 2.23-2.05 (m, 2H), 1.98 (s, 3H),1.39 (s, 19H), 1.24-1.13 (m, 4H); ¹³C NMR (101 MHz, cdcl₃) δ 167.1,158.3, 132.5, 131.5, 126.9, 126.9, 126.8, 125.6, 125.6, 119.8, 113.3,110.0, 77.2, 68.8, 49.5, 31.9, 29.7, 28.1, 28.0, 22.7, 14.1.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(3-(trifluoromethyl)-4-(((Z)-3-(4-(trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 10.10 (s, 2H), 8.30 (d, J=2.1 Hz, 1H),8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.69-7.61 (m, 2H), 7.42-7.34 (m, 2H), 6.94(d, J=8.7 Hz, 1H), 6.80 (d, J=11.8 Hz, 1H), 6.10 (dt, J=11.8, 6.4 Hz,1H), 5.61 (dd, J=7.8, 4.5 Hz, 1H), 4.91 (dd, J=6.4, 1.7 Hz, 2H), 3.90(dt, J=11.4, 7.0 Hz, 1H), 3.85-3.75 (m, 1H), 2.55-2.39 (m, 1H), 2.20 (s,2H), 2.11-1.96 (m, 1H), 1.61-1.36 (m, 15H), 1.27 (s, 3H).

tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(4-(3-(trifluoromethyl)-4-(((E)-4-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)oxy)phenyl)oxazol-2-yl)pyrrolidin-1-yl)methylene)carbamate

¹H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J=2.1 Hz, 1H), 8.18 (dd,J=8.7, 2.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.06(d, J=8.7 Hz, 1H), 6.58 (s, 0H), 6.54 (s, 1H), 6.42 (dt, J=15.9, 6.9 Hz,1H), 5.58 (dd, J=7.8, 4.6 Hz, 1H), 4.23 (t, J=6.2 Hz, 2H), 3.88 (dt,J=11.5, 7.0 Hz, 1H), 3.83-3.70 (m, 1H), 2.77 (qd, J=6.3, 1.3 Hz, 2H),2.42 (ddd, J=15.7, 10.4, 6.8 Hz, 2H), 2.24-2.12 (m, 2H), 2.07-1.96 (m,2H); ¹³C NMR (101 MHz, cdcl₃) δ 179.2, 167.1, 158.8, 140.7, 140.7,132.5, 131.6, 129.2, 128.9, 128.2, 126.8, 126.8, 126.7, 126.2, 125.6,125.5, 125.5, 125.4, 125.4, 124.6, 121.8, 119.6, 119.3, 118.9, 112.8,77.2, 68.2, 55.3, 49.5, 32.6, 29.7, 28.1, 28.1, 28.0, 24.0, 14.1.

tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(3-(4-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamatecompound 77

¹H NMR (400 MHz, Chloroform-d) δ 10.10 (s, 2H), 8.28 (d, J=2.1 Hz, 1H),8.18 (dd, J=8.7, 2.3 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 5.60 (dd, J=7.8,4.5 Hz, 1H), 5.52-5.43 (m, 1H), 4.71 (d, J=6.4 Hz, 1), 3.98-3.74 (m,2H), 2.52-2.39 (m, 2H), 2.28-1.99 (m, 6H), 1.71 (s, 3H), 1.72-1.31 (m,24H); ¹³C NMR (101 MHz, cdcl₃) δ 181.5, 181.0, 166.8, 158.4, 154.3,153.4, 150.6, 149.3, 148.8, 135.9, 135.7, 135.5, 135.3, 131.4, 130.4,128.8, 128.7, 126.7, 126.3, 125.5, 125.1, 123.9, 123.2, 121.2, 80.6,77.3, 77.2, 77.0, 76.7, 70.9, 70.8, 63.7, 63.3, 53.8, 53.8, 46.6, 46.4,38.6, 37.6, 34.4, 34.3, 32.4, 32.1, 32.0, 31.5, 31.4, 31.4, 29.7, 28.3,28.1, 26.4, 26.2, 24.4, 23.7, 22.0; Calcd for C₃₄H₄₈ClF₃N₅O₆ [M+H]⁺:714.324, Found: 714.3307.

(S)-2-(3-(4-(allyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride

¹H NMR (500 MHz, Methanol-d₄) δ 8.14 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.5Hz, 1H), 5.98 (ddt, J=17.3, 10.7, 4.9 Hz, 1H), 5.41-5.31 (m, 2H), 5.22(q, J=1.5 Hz, 1H), 4.67 (dt, J=4.9, 1.7 Hz, 2H), 3.68 (td, J=9.2, 2.6Hz, 1H), 3.52 (td, J=9.6, 7.2 Hz, 1H), 2.53-2.30 (m, 2H), 2.15-2.01 (m,1H), 1.81-1.99 (m, 1H); ¹³C NMR (126 MHz, MeOD) δ 177.8, 167.1, 158.8,155.7, 132.5, 132.5, 132.0, 125.7, 124.3, 122.2, 119.2, 118.3, 116.6,113.9, 69.2, 55.0, 48.1, 47.9, 47.9, 47.8, 47.7, 47.6, 47.6, 47.4, 47.3,47.1, 31.3, 22.9; Found [M+H]⁺ 345.0.

Example 84:(S)-2-(3-(4-(but-3-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (compound 79A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.30-8.15 (m, 2H), 7.33 (d, J=8.3 Hz,1H), 6.01-5.85 (m, 1H), 5.48-5.37 (m, 1H), 5.23-5.17 (m, 1H), 5.12-5.06(m, 1H), 4.21 (t, J=6.2 Hz, 2H), 3.77 (t, J=8.6 Hz, 1H), 3.69-3.52 (m,1H), 2.63-2.42 (m, 4H), 2.31-2.01 (m, 2H); ¹³C NMR (101 MHz,Methanol-d₄) δ 177.8, 167.1, 159.2, 155.6, 133.9, 132.5, 125.6, 124.6,121.9, 119.0, 118.1, 113.5, 68.4, 55.1, 48.2, 48.2, 48.0, 47.8, 47.6,47.4, 47.2, 47.0, 33.0, 31.4; Found [M+H]⁺ 360.0.

Example 85:(S)-amino(2-(3-(4-(hex-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (Compound 80A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.26-8.18 (m, 1.6H), 8.16-8.13 (m,0.4H), 8.09-8.01 (m, 0.4H), 7.35-7.28 (m, 1H), 7.09-7.02 (d, J=8.5 Hz,0.4H), 6.00-5.84 (m, 1H), 5.80-5.52 (m, 1H), 5.48-5.32 (m, 1H),4.72-4.65 (m, 1H), 3.76 (td, J=9.2, 2.6 Hz, 1H), 3.70-3.51 (m, 1H),2.68-2.37 (m, 2H), 2.30-2.00 (m, 1H), 1.42 (h, J=7.3 Hz, 1H), 0.90 (q,J=7.5 Hz, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ 190.0, 188.1, 175.9,167.6, 159.9, 139.5, 136.3, 132.0, 110.0, 99.9, 99.3, 69.2, 63.9, 55.0,45.6, 31.3, 22.9, 12.8. Found [M+H]⁺ 424.1955.

Example 86:(S)-amino(2-(3-(4-(hept-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (Compound 81A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.25-8.19 (m, 1.5H), 8.15-8.13 (m,0.5H), 8.05-8.08 (m, 0.5H), 7.38-7.21 (d, J=8.5 Hz, 1H), 7.07-7.03 (m,=8.6, 0.7 Hz, 1H), 5.97-5.84 (m, 1H), 5.74-5.62 (m, 1H), 5.41-5.38 (m,J=7.9, 4.1, 1.9 Hz, 2H), 4.71-4.63 (m, J=1H), 3.81-3.73 (td, J=9.2, 2.6Hz, 2H), 3.59 (q, J=9.2 Hz, 2H), 2.60-2.40 (m, 2H), 2.21-2.08 (m, 2H),2.16-2.00 (m, 3H), 1.44-1.24 (m, 4H), 0.94-0.84 (m, 3H); ¹³C NMR (101MHz, Methanol-d₄) δ 190.0, 175.9, 159.9, 157.8, 139.5, 136.3, 132.0,110.0, 99.9, 80.9, 69.2, 63.9, 55.0, 45.6, 41.8, 31.3, 22.9.

Example 87:(S)-amino(2-(3-(4-(oct-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (Compound 82A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.31-8.12 (m, 2H), 7.38-7.27 (m, 1H),5.97-5.84 (m, 1H), 5.76-5.59 (m, 1H), 5.42 (dd, J=7.9, 2.0 Hz, 1H), 4.69(dq, J=5.8, 1.2 Hz, 2H), 2.64-2.42 (m, 2H), 2.30-1.94 (m, 4H), 1.61-1.14(m, 11H), 0.97-0.81 (m, 4H); ¹³C NMR (126 MHz, MeOD) δ 177.8, 167.2,159.0, 155.7, 135.8, 135.4, 132.3, 125.7, 124.3, 123.6, 123.1, 118.1,114.2, 69.3, 55.0, 48.1, 47.9, 47.8, 47.6, 47.4, 47.2, 47.1, 31.0, 29.4,28.4, 26.7, 22.9, 22.1, 12.9. ESI found [M+H]⁺ 452.2285.

Example 88:(S,E)-amino(2-(3-(4-(hept-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (Compound 78A)

¹H NMR (400 MHz, Chloroform-d) δ 8.31-8.23 (m, 2H), 7.48-7.28 (m, 1H),6.03-5.81 (m, 1H), 5.76-5.41 (m, 1H), 5.48 (dd, J=7.9, 2.0 Hz, 1H), 4.75(dd, J=5.8, 1.3 Hz, 2H), 3.82 (td, J=9.1, 2.7 Hz, 1H), 3.66 (td, J=9.6,7.3 Hz, 1H), 2.68-2.47 (m, 2H), 2.34-2.22 (m, 1H), 2.16 (q, J=7.0 Hz,3H), 1.50-1.30 (m, 4H), 1.00-0.90 (m, 3H); ¹³C NMR (101 MHz,Methanol-d₄) δ 187.5, 177.8, 167.1, 147.2, 135.7, 132.3, 128.2, 123.6,114.1, 69.3, 55.0, 48.2, 48.0, 47.8, 47.6, 47.3, 47.1, 46.9, 30.9, 22.9,21.7, 12.8; ESI found [M+H]⁺ 438.0.

Example 89:(S,E)-amino(2-(3-(4-(oct-2-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (Compound 83A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.23-8.19 (m, 2H), 7.32 (d, J=8.6 Hz,1H), 5.96-5.85 (m, 1H), 5.66 (dtt, J=15.5, 5.8, 1.4 Hz, 1H), 5.42 (dd,J=7.9, 2.0 Hz, 1H), 4.69 (dd, J=5.8, 1.2 Hz, 2H), 3.80-3.71 (m, 1H),3.59 (td, J=9.7, 7.2 Hz, 1H), 2.63-2.38 (m, 3H), 2.29-1.97 (m, 5H),1.50-1.17 (m, 7H), 0.97-0.74 (m, 3H); ¹³C NMR (101 MHz, Methanol-d₄) δ187.5, 177.8, 167.1, 159.0, 155.7, 147.3, 135.8, 132.3, 132.3, 128.2,125.7, 124.6, 123.6, 123.6, 121.9, 119.3, 118.1, 114.1, 69.2, 55.0,48.2, 48.0, 47.8, 47.6, 47.5, 47.3, 47.2, 47.1, 46.9, 31.8, 31.3, 28.3,22.9, 22.1; ESI found [M+H]⁺ 452.2285

Example 90:(S,Z)-amino(2-(3-(4-(hept-3-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (Compound 84)

¹H NMR (500 MHz, Methanol-d₄) δ 8.33-8.09 (m, 2H), 7.33 (d, J=8.7 Hz,1H), 5.72-5.18 (m, 3H), 4.18 (t, J=6.5 Hz, 2H), 3.84-3.73 (m, 1H), 3.61(td, 9.7, 7.2 Hz, 1H), 2.63-2.41 (m, 4H), 2.22 (dtd, J=10.9, 4.9, 4.4,2.4 Hz, 1H), 2.13-2.02 (m, 2H), 1.39 (p, J=7.4 Hz, 2H), 0.92 (t, J=7.4Hz, 3H); ¹³C NMR (126 MHz, MeOD) δ 177.8, 167.1, 159.3, 155.7, 132.5,132.0, 125.7, 124.4, 118.1, 113.5, 113.5, 68.7, 55.0, 48.1, 47.9, 47.8,47.6, 47.5, 47.4, 47.4, 47.2, 47.1, 31.3, 26.7, 22.9; ESI found [M+H]⁺438.2104.

Example 91:(S,Z)-amino(2-(3-(4-(oct-3-en-1-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (Compound 85A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.52-8.07 (m, 2H), 7.49-7.28 (m, 1H),5.77-5.30 (m, 2H), 4.38-4.15 (m, 2H), 3.81-3.01 (m, 2H), 2.85-1.87 (m,8H), 1.62-0.70 (m, 7H); ¹³C NMR (101 MHz, Methanol-d₄) δ 187.5, 177.8,167.1, 159.3, 155.7, 132.5, 132.5, 132.2, 132.2, 125.7, 124.2, 124.2,121.9, 118.8, 118.1, 68.7, 68.7, 55.0, 55.0, 48.2, 48.0, 48.0, 47.8,47.6, 47.4, 47.1, 46.9, 31.5, 31.5, 31.3, 31.3, 26.7, 26.6, 22.9, 22.9,21.9, 21.9, 12.9; ESI found [M+H]⁺ 452.2260.

Example 92:(S,E)-2-(3-(4-((3-(3-bromophenyl)allyl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (Compound 86A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.40-8.13 (m, 1H), 7.59 (t, J=1.9 Hz,0H), 7.48-7.31 (m, 1H), 7.32-7.13 (m, 0H), 6.88-6.70 (m, 0H), 6.49 (dt,J=16.0, 5.4 Hz, 0H), 5.42 (dd, J=7.8, 2.0 Hz, 0H), 4.86 (s, 10H), 3.76(td, J=9.2, 2.6 Hz, 1H), 3.59 (td, J=9.7, 7.3 Hz, 1H), 2.65-2.42 (m,1H), 2.32-2.14 (m, OH), 2.06 (ddd, J=11.8, 9.4, 5.2 Hz, 1H); ¹³C NMR(101 MHz, Methanol-d₄) δ 177.8, 167.1, 158.8, 155.6, 138.7, 132.5,131.2, 130.0, 129.0, 125.8, 124.9, 122.3, 118.4, 114.0, 68.9, 55.0,48.2, 48.0, 47.8, 47.7, 47.6, 47.3, 47.1, 46.9, 31.3, 22.9.

Example 93:(S,E)-2-(3-(4-((3-(4-fluorophenyl)allyl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (Compound 87A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.22 (d, J=6.6 Hz, 2H), 7.54-7.28 (m,3H), 7.04 (q, J=8.3 Hz, 2H), 6.79 (d, J=15.5 Hz, 1H), 6.39 (d, J=15.0Hz, 1H), 5.42 (s, 1H), 3.86-3.52 (m, 3H), 2.50 (d, J=37.7 Hz, 2H),2.18-2.13 (m, 2H), 1.50 (d, J=7.0 Hz, 2H); ¹³C NMR (101 MHz,Methanol-d4) δ 147.4, 140.4, 138.1, 131.7, 131.5, 130.6, 129.1, 128.1,128.1, 127.9, 125.1, 123.3, 100.7, 61.0, 48.2, 48.0, 47.8, 47.5, 47.3,47.1, 46.9. ESI found [M+H]⁺ 476.1715.

Example 94:(S,E)-2-(3-(3-(trifluoromethyl)-4-((3-(2-(trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (Compound 89A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.28-8.24 (m, 2H), 7.76 (d, J=7.9 Hz,1H), 7.65 (d, J=7.8 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.47-7.36 (m, 2H),7.20 (dd, J=16.1, 2.8 Hz, 1H), 6.48 (dt, J=15.8, 4.5 Hz, 1H), 5.47-5.40(m, 1H), 4.98 (dd, J=4.6, 2.0 Hz, 2H), 3.80-3.56 (m, 2H), 2.62-2.43 (m,2H), 2.26-2.20 (m, 1H), 2.13-2.01 (m, 1H); ¹³C NMR (101 MHz,Methanol-d₄) δ 187.6, 177.8, 167.1, 158.4, 155.7, 135.4, 132.4, 132.0,127.5, 127.4, 127.2, 125.8, 125.8, 125.7, 125.3, 125.3, 118.5, 114.0,68.3, 55.1, 48.2, 48.0, 47.8, 47.6, 47.4, 47.1, 46.9, 31.3, 26.7, 22.9;ESI found [M+H]⁺ 526.1653.

Example 95:(S,E)-amino(2-(3-(3-(trifluoromethyl)-4-((3-(3-(trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (Compound 90A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.30-8.22 (m, 1H), 7.70 (d, J=8.4 Hz,2H), 7.59-7.49 (m, 2H), 7.48-7.33 (m, 2H), 6.89 (d, J=16.1 Hz, 1H), 6.59(dt, J=16.1, 5.3 Hz, 1H), 5.43 (dd, J=7.9, 1.9 Hz, 1H), 4.96 (dd, J=5.3,1.6 Hz, 2H), 3.82-3.50 (m, 4H), 2.60-2.39 (m, 2H), 2.23 (dd, J=12.9, 6.9Hz, 1H), 2.14-2.01 (m, 1H); ¹³C NMR (101 MHz, Methanol-d4) δ 177.8,167.1, 158.8, 155.7, 137.4, 132.5, 131.1, 129.6, 129.1, 127.9, 125.8,125.3, 124.0, 122.7, 119.3, 118.5, 114.0, 68.9, 55.0, 48.2, 48.0, 47.8,47.6, 47.4, 47.2, 46.9, 31.3, 22.9. ESI found [M+H]⁺ 526.0.

Example 96:(S,E)-amino(2-(3-(3-(trifluoromethyl)-4-((3-(4-(trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (Compound 88A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.26 (d, J=11.0 Hz, 2H), 7.62 (s, 3H),7.41 (d, J=8.5 Hz, 1H), 6.92-6.85 (m, 1H), 6.64 (t, J=5.2 Hz, 0.5H),6.60 (t, J=5.3 Hz, 0.5H), 5.42 (d, J=9.7 Hz, 1H), 4.96 (d, J=6.6 Hz,2H), 3.76 (t, J=9.1 Hz, 1H), 3.66-3.53 (m, 1H), 2.62-2.40 (m, 2H),2.28-2.15 (m, 1H), 2.15-2.00 (m, 1H); ¹³C NMR (101 MHz, Methanol-d₄) δ174.9, 167.2, 158.9, 140.2, 132.6, 131.1, 126.6, 126.6, 125.2, 118.1,114.1, 68.8, 54.1, 48.2, 48.0, 47.8, 47.6, 47.3, 47.3, 47.1, 46.9, 46.0,28.8, 23.1; ESI found [M+H]⁺ 526.1672.

Example 97:(S,Z)-amino(2-(3-(3-(trifluoromethyl)-4-((3-(4-(trifluoromethyl)phenyl)allyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methaniminium2,2,2-trifluoroacetate (Compound 92A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.30-8.17 (m, 2H), 7.77-7.66 (m, 2H),7.58-7.45 (m, 2H), 7.25 (d, J=8.7 Hz, 1H), 6.86 (d, J=11.8 Hz, 1H), 6.12(dt, J=11.8, 6.3 Hz, 1H), 5.44 (dd, J=7.9, 1.9 Hz, 1H), 5.01 (dd, J=6.3,1.7 Hz, 2H), 3.77 (ddd, J=11.3, 8.7, 2.6 Hz, 1H), 3.61 (td, J=9.6, 7.2Hz, 1H), 2.65-2.40 (m, 2H), 2.33-2.00 (m, 2H).

Example 98:(S,E)-2-(3-(3-(trifluoromethyl)-4-((4-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (Compound 91A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.30-8.14 (m, 2H), 7.55 (q, J=8.3 Hz,4H), 7.37 (d, J=8.4 Hz, 1H), 6.64 (d, J=15.9 Hz, 1H), 6.57-6.46 (m, 1H),5.49-5.37 (m, 1H), 4.33 (t, J=6.0 Hz, 2H), 3.84-3.49 (m, 2H), 2.77 (q,J=6.1 Hz, 2H), 2.54-2.48 (m, 2H), 2.31-1.95 (m, 2H); ¹³C NMR (101 MHz,cd₃od) δ 177.8, 167.1, 159.1, 155.6, 141.3, 132.6, 131.1, 131.1, 128.6,128.6, 126.1, 125.0, 118.2, 113.6, 72.2, 71.0, 68.2, 68.2, 60.8, 55.1,48.2, 48.0, 47.8, 47.7, 47.6, 47.4, 47.2, 47.0, 32.2, 32.2, 31.4, 26.7,23.0, 18.0; Calc for C₂₅H₂₃F₆N₅O₂ [M+H]⁺: 539.1756, Found: 540.0.

Example 99:(S,E)-(2-(3-(4-((3,7-dimethylocta-2,6-dien-1-yl)oxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)(13-iodanylidene)methanaminehydrochloride (Compound 93A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.25-8.17 (m, 1H), 8.15-8.12 (m, 1H),8.09-8.03 (m, 1H), 7.31 (d, J=8.7 Hz, 0.4H), 7.07 (d, J=8.6 Hz, 0.6H),5.51-5.45 (m, 0.4H), 5.44-5.38 (m, 0.6H), 4.81-4.75 (m, 1H), 3.82-3.66(m, 1H), 3.63-3.54 (m, 1H), 3.27-3.14 (m, 1H), 2.61-2.39 (m, 2H),2.29-1.99 (m, 3H), 1.79-1.75 (m, 1H), 1.67-1.59 (m, 1H), 1.57-1.44 (m,3H), 1.39-1.26 (m, 2H).

Example 100: tert-butyl(S)-2-(3-(4-((4-propoxyphenyl)ethynyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.37 (d, J=1.6 Hz, 1H), 8.18 (d, J=8.2Hz, 1H), 7.71 (t, J=8.2 Hz, 1H), 7.53-7.40 (m, 2H), 6.93-6.82 (m, 2H),5.21-5.01 (m, 1H), 3.93 (t, J=6.6 Hz, 2H), 3.71 (q, J=5.9 Hz, 1H),3.41-3.59 (m, 1H), 2.49-2.27 (m, 1H), 2.21-1.95 (m, 3H), 1.76-1.87 (m,2H), 1.45 (s, 3H), 1.26 (s, 7H), 1.03 (t, J=7.4 Hz, 3H); ¹³C NMR (101MHz, cdcl₃) δ 167.1, 160.0, 133.9, 133.8, 133.4, 129.9, 124.9, 114.6,114.1, 84.0, 80.6, 69.6, 53.8, 46.6, 46.3, 32.4, 31.4, 29.7, 28.3, 28.1,24.4, 23.7, 22.5, 10.5.

Example 101: tert-butyl(S)-2-(3-(4-(4-propoxyphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

¹H NMR (500 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.13 (t, J=8.3 Hz, 1H),7.41-7.32 (m, 1H), 7.15-7.07 (m, 2H), 6.87-6.81 (m, 2H), 5.25-5.04 (m,1H), 3.91 (t, J=6.6 Hz, 2H), 3.79-3.65 (m, 1H), 3.64-3.45 (m, 1H), 3.10(t, J=8.3 Hz, 2H), 2.87 (t, J=8.3 Hz, 2H), 2.48-2.31 (m, 1H), 2.24-2.09(m, 2H), 2.05-1.95 (m, 1H), 1.81 (q, J=6.9 Hz, 2H), 1.47 (s, 3H), 1.31(s, 6H), 1.04 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, cdcl₃) δ 181.0,167.4, 157.6, 143.8, 132.8, 132.0, 131.9, 130.3, 129.3, 125.2, 114.5,80.5, 77.2, 69.5, 53.8, 46.6, 46.3, 36.9, 35.3, 32.4, 31.5, 31.2, 29.7,28.3, 28.1, 24.4, 23.7, 22.6, 14.1, 10.5.

Example 102: tert-butyl(S,Z)-(((tert-butoxycarbonyl)amino)(2-(3-(4-(4-propoxyphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)methylene)carbamate

¹H NMR (500 MHz, Chloroform-d) δ 8.34 (d, J=1.7 Hz, 1H), 8.13 (dd,J=8.1, 1.7 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.14-7.07 (m, 2H), 6.88-6.78(m, 2H), 5.71 (s, 1H), 3.91 (t, J=6.6 Hz, 4H), 3.10 (dd, J=9.8, 6.6 Hz,2H), 2.92-2.83 (m, 2H), 2.49 (s, 1H), 2.23 (s, 2H), 2.02-2.15 (m, 1H),f1.85-1.75 (m, 2H)i, 1.46 (s, 18H), 1.04 (t, J=7.4 Hz, 3H)

Example 103:(S)-2-(3-(4-(4-propoxyphenethyl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamidehydrochloride (Compound 94A)

¹H NMR (400 MHz, Methanol-d₄) δ 8.29 (d, J=1.6 Hz, 1H), 8.17 (dd, J=8.0,1.7 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.09 (d, J=8.5 Hz,2H), 6.82 (d, J=8.5 Hz, 2H), 5.46 (d, J=7.3 Hz, 1H), 3.89 (t, J=6.5 Hz,2H), 3.78 (t, J=8.8 Hz, 1H), 3.62 (q, J=9.0 Hz, 1H), 3.15-3.05 (m, 2H),2.91-2.82 (m, 2H), 2.63-2.43 (m, 2H), 2.31-2.05 (m, 2H), 1.81-1.71 (m,2H), 1.03 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, cd₃od) δ 178.1, 167.2,157.7, 155.7, 144.2, 132.6, 130.2, 129.0, 128.6, 125.6, 124.4, 124.4,124.3, 122.9, 114.1, 69.1, 55.1, 48.2, 48.0, 47.8, 47.6, 47.4, 47.1,46.9, 36.5, 34.9, 31.3, 22.9, 22.3, 9.4.

Example 104: tert-butyl(S,E)-2-(4-(3-(trifluoromethyl)-4-((4-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)oxy)phenyl)oxazol-2-yl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J=2.2 Hz, 1H), 8.23-8.17 (m,1H), 7.55 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.08 (t, J=9.1 Hz,1H), 6.58 (d, J=15.9 Hz, 1H), 6.43 (dt, J=15.9, 6.9 Hz, 1H), 5.23-5.14(m, 1H), 5.06 (dd, J=8.2, 3.7 Hz, 1H), 4.24 (t, J=6.1 Hz, 2H), 3.77-3.44(m, 3H), 2.78 (q, J=6.4 Hz, 2H), 2.31-2.45 (m, 1H), 2.04-2.21 (m, 2H),2.06-1.92 (m, 1H), 1.46 (s, 3H), 1.29 (s, 6H); ¹³C NMR (101 MHz, cdcl₃)δ 199.7, 180.9, 174.5, 167.2, 167.2, 158.8, 153.5, 140.7, 132.4, 131.6,128.2, 126.8, 126.2, 125.5, 125.4, 125.4, 122.8, 118.9, 118.9, 112.9,80.5, 77.2, 77.0, 68.2, 53.8, 46.6, 46.3, 32.6, 32.4, 31.5, 28.3, 28.1,24.4, 23.7.

Example 105: tert-butyl((E)-((tert-butoxycarbonyl)amino)((S)-2-(4-(3-(trifluoromethyl)-4-(((E)-4-(4-(trifluoromethyl)phenyl)but-3-en-1-yl)oxy)phenyl)oxazol-2-yl)pyrrolidin-1-yl)methylene)carbamate(10)

¹H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J=2.1 Hz, 1H), 8.18 (dd,J=8.7, 2.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.06(d, J=8.7 Hz, 1H), 6.58 (s, 0H), 6.54 (s, 1H), 6.42 (dt, J=15.9, 6.9 Hz,1H), 5.58 (dd, J=7.8, 4.6 Hz, 1H), 4.23 (t, J=6.2 Hz, 2H), 3.88 (dt,J=11.5, 7.0 Hz, 1H), 3.83-3.70 (m, 1H), 2.77 (qd, J=6.3, 1.3 Hz, 2H),2.42 (ddd, J=15.7, 10.4, 6.8 Hz, 2H), 2.24-2.12 (m, 2H), 2.07-1.96 (m,2H); ¹³C NMR (101 MHz, cdcl₃) δ 179.2, 167.1, 158.8, 140.7, 140.7,132.5, 131.6, 129.2, 128.9, 128.2, 126.8, 126.8, 126.7, 126.2, 125.6,125.5, 125.5, 125.4, 125.4, 124.6, 121.8, 119.6, 119.3, 118.9, 112.8,77.2, 68.2, 55.3, 49.5, 32.6, 29.7, 28.1, 28.1, 28.0, 24.0, 14.1.

Example 106: 4-(3-cyclohexylpropoxy)-3-(trifluoromethyl)benzonitrile

Synthesized by General Procedure A. 89% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 7.85 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.7, 2.1 Hz,1H), 7.05 (d, J=8.7 Hz, 1H), 4.09 (t, J=6.4 Hz, 2H), 1.89-1.81 (m, 2H),1.76-1.61 (m, 5H), 1.39-1.09 (m, 6H), 0.99-0.83 (m, 2H).

Example 107: tert-butyl(2S,3S)-2-(3-(4-(3-cyclohexylpropoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 79% yield, white solid; ¹HNMR (600 MHz, Chloroform-d) δ 8.29-8.24 (m, 1H), 8.20-8.13 (m, 1H),7.09-7.01 (m, 1H), 5.13-4.93 (m, 1H), 4.60-4.54 (m, 1H), 4.15-4.05 (m,2H), 3.82-3.67 (m, 2H), 2.48 (s, 0H), 2.40-2.28 (m, 1H), 2.08-2.01 (m,1H), 1.89-1.81 (m, 2H), 1.77-1.59 (m, 6H), 1.47 (s, 3H), 1.40-1.33 (m,2H), 1.32-1.10 (m, 10H), 0.97-0.85 (m, 2H).

Example 108: tert-butyl((E)-((tert-butoxycarbonyl)imino)((2S,3S)-2-(3-(4-(3-cyclohexylpropoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-1-yl)methyl)carbamate

Synthesized by General Procedure D. 31% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 8.26 (d, J=2.1 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz,1H), 7.05 (d, J=8.7 Hz, 1H), 5.61 (s, 1H), 4.73-4.68 (m, 1H), 4.13-4.05(m, 3H), 3.98-3.91 (m, 1H), 2.39-2.30 (m, 1H), 2.19-2.11 (m, 1H),1.89-1.81 (m, 2H), 1.77-1.66 (m, 4H), 1.68-1.62 (m, 1H), 1.47 (s, 18H),1.40-1.33 (m, 2H), 1.31-1.12 (m, 5H), 0.97-0.87 (m, 2H).

Example 109:amino((2S,3S)-2-(3-(4-(3-cyclohexylpropoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-1-yl)methaniminiumchloride (Compound 95A)

Synthesized by General Procedure E. 84% yield, white solid; ¹H NMR (600MHz, Methanol-d₄) δ 8.28-8.19 (m, 2H), 7.32 (d, J=8.7 Hz, 1H), 5.25 (t,J=1.0 Hz, 1H), 4.81-4.76 (m, 1H), 4.16 (t, J=6.2 Hz, 2H), 3.89-3.78 (m,2H), 2.28-2.14 (m, 2H), 1.84 (ddt, J=10.1, 8.2, 6.1 Hz, 2H), 1.80-1.62(m, 6H), 1.44-1.25 (m, 6H), 0.99-0.90 (m, 2H); ¹³C NMR (151 MHz, cd₃od)δ 176.97, 168.69, 160.92, 157.58, 133.97, 127.12, 127.08, 125.61,123.80, 120.38, 120.17, 119.23, 114.85, 75.99, 70.67, 64.80, 47.42,38.58, 34.66, 34.46, 32.48, 27.75, 27.42, 27.40; HRMS (ESI+): Calc'd forC₂₃H₃₁F₃N₅O₃ [M+H]: 482.2379, Found: 482.2369.

Example 110: 4-(cyclohexylmethoxy)-3-(trifluoromethyl)benzonitrile

Synthesized by General Procedure A. 90% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 7.85 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.7, 2.1 Hz,1H), 7.04 (d, J=8.7 Hz, 1H), 3.90 (d, J=5.7 Hz, 2H), 1.91-1.67 (m, 6H),1.36-1.05 (m, 5H).

Example 111: tert-butyl(2S,3S)-2-(3-(4-(cyclohexylmethoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidine-1-carboxylate

Synthesized by General Procedures B and C. 80% yield, white solid; ¹HNMR (600 MHz, Chloroform-d) δ 8.29-8.23 (m, 1H), 8.19-8.12 (m, 1H),7.08-7.00 (m, 1H), 5.12-4.93 (m, 1H), 4.61-4.54 (m, 1H), 3.92-3.87 (m,2H), 3.83-3.67 (m, 2H), 2.41-2.27 (m, 2H), 2.09-2.01 (m, 1H), 1.90-1.81(m, 3H), 1.82-1.68 (m, 3H), 1.47 (s, 3H), 1.37-1.16 (m, 9H), 1.16-1.06(m, 2H).

Example 112: tert-butyl((E)-((tert-butoxycarbonyl)imino)((2S,3S)-2-(3-(4-(cyclohexylmethoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-1-yl)methyl)carbamate

Synthesized by General Procedure D. 38% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 8.25 (d, J=2.1 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz,1H), 7.04 (d, J=8.8 Hz, 1H), 5.63-5.59 (m, 1H), 4.73-4.68 (m, 1H),4.13-4.05 (m, 1H), 3.97-3.88 (m, 3H), 2.39-2.30 (m, 1H), 2.20-2.11 (m,1H), 1.91-1.83 (m, 3H), 1.82-1.74 (m, 2H), 1.75-1.68 (m, 1H), 1.47 (s,18H), 1.37-1.23 (m, 3H), 1.25-1.17 (m, 1H), 1.16-1.07 (m, 2H).

Example 112:amino((2S,3S)-2-(3-(4-(cyclohexylmethoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-hydroxypyrrolidin-1-yl)methaniminiumchloride (Compound 96A)

Synthesized by General Procedure E. 92% yield, white solid; ¹H NMR (600MHz, Methanol-d₄) δ 8.27-8.19 (m, 2H), 7.31 (d, J=8.7 Hz, 1H), 5.25 (t,=1.0 Hz, 1H), 4.81-4.77 (m, 1H), 3.98 (d, J=5.9 Hz, 2H), 3.89-3.79 (m,2H), 2.28-2.14 (m, 2H), 1.92-1.69 (m, 6H), 1.41-1.12 (m, 6H); ¹³C NMR(151 MHz, cd₃od) δ 176.97, 168.68, 160.98, 157.58, 134.00, 127.15,127.10, 127.06, 127.03, 125.64, 123.83, 120.03, 119.17, 114.73, 75.99,75.53, 68.12, 64.79, 47.42, 38.93, 32.48, 30.57, 27.51, 26.91; HRMS(ESI+): Calc'd for C₂₁H₂₇F₃N₅O₃ [M+H]: 454.2066, Found: 454.2060.

Synthesis of N-hydroxlated Compounds of Formula I

General Procedure AA. Nucleophilic Aromatic Substitution

4-fluoro-3-(trifluoromethyl)benzonitrile (1 equiv) and the alcohol (1equiv) were added to a microwave vial and cooled in an ice bath, then0.5M potassium tert-butoxide in tetrahydrofuran (1.1 equiv) wascarefully added and allowed to warm to room temperature. The contentswere then heated to 115° C. for 1 minute in the microwave. Aftercooling, celite was added and the solvent was removed under reducedpressure. The resulting powder was subjected to flash chromatography onsilica gel.

General Procedure BB. Conversion of Nitrile to Amidoxime

The nitrile (1 equiv) and hydroxylamine hydrochloride (2.2 equiv) weresuspended in absolute ethanol. Triethylamine (2.3 equiv) was added andthe contents were heated to 70° C. for 3 hours. Multi-gram scalereactions were heated overnight. Upon cooling, the solvent wasevaporated under reduced pressure. To the resulting residue, ethylacetate and saturated NaHCO₃ solution were added and stirred until allresidue was dissolved. The mixture was transferred to a separatoryfunnel and the aqueous layer was discarded. The organic layer was washedwith brine, dried over Na₂SO₄, filtered, and concentrated to provide theproduct in sufficiently pure form to be used without furtherpurification.

General Procedure CC. PyBOP-Mediated Oxadiazole Formation

The carboxylic acid (1.1 equiv) and PyBOP (1.2 equiv) were dissolved indry N,N-dimethylformamide. N,N-diisopropylethylamine (3 equiv) was addedand stirred for 15 minutes at room temperature. The amidoxime (1 equiv)dissolved in minimal N,N-dimethylformamide was added and the mixture wasstirred for 4 hours at room temperature, then heated to 100° C.overnight. The mixture was allowed to cool to room temperature, thenpoured into a separatory funnel and diluted with ethyl acetate. Theorganics were washed with saturated NaHCO₃, followed by brine. Thebicarbonate wash was back-extracted with ethyl acetate and all organicswere combined, dried over Na₂SO₄ and filtered. Celite was added to theflask and the solvent was evaporated under reduced pressure. Theresulting powder was subjected to flash chromatography on silica gel.

General Procedure DD. Cyanamide Formation

The Boc-protected pyrrolidine was dissolved in 4M HCl in dioxane andheated to 100° C. in the microwave for 1 minute. The solvent wasevaporated and the crude reconstituted in dry dichloromethane. 3MCyanogen bromide in dichloromethane (0.95 equiv) was added, followed bytriethylamine (3 equiv) and the mixture was stirred at room temperatureovernight. Saturated NaHCO₃ was carefully added, and the mixture wastransferred to a seperatory funnel and diluted with ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄, and filtered.Celite was added and the solvent was evaporated under reduced pressure.The resulting powder was subjected to flash chromatography on silicagel.

General Procedure EE. Hydroxyguanidine Formation

The cyanamide (1 equiv) and hydroxylamine hydrochloride (2.2 equiv) weresuspended in absolute ethanol. Triethylamine (2.3 equiv) was added andthe mixture was stirred at 70° C. for 16 hours. Celite was added and thesolvent was evaporated under reduced pressure. The resulting powder wassubjected to flash chromatography on a Biotage KP-NH column.

4-(octyloxy)-3-(trifluoromethyl)benzonitrile

Synthesized by General Procedure AA. 96% yield, colorless oil; ¹H NMR(600 MHz, Chloroform-d) δ 7.85 (d, J=2.1 Hz, 1H), 7.77 (dd, J=8.7, 2.1Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 1.88-1.80 (m,2H), 1.47 (p, J=7.5, 7.1 Hz, 2H), 1.38-1.24 (m, 8H), 0.88 (t, J=6.8 Hz,3H).

N-hydroxy-4-(octyloxy)-3-(trifluoromethyl)benzimidamide

Synthesized by General Procedure BB. 100% yield, white solid; ¹H NMR(600 MHz, Chloroform-d) δ 9.25 (s, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.72(dd, J=8.7, 2.3 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 4.98 (s, 2H), 4.03 (t,J=6.4 Hz, 2H), 1.81 (tt, J=12.4, 6.4 Hz, 2H), 1.46 (p, J=7.7, 7.3 Hz,2H), 1.40-1.23 (m, 8H), 0.89 (t, J=6.8 Hz, 3H).

tert-butyl(2S,3S)-3-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedure CC. 87% yield, colorless oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.29-8.24 (m, 1H), 8.20-8.12 (m, 1H),7.09-7.02 (m, 1H), 5.12-4.93 (m, 1H), 4.61-4.54 (m, 1H), 4.10 (q, J=6.6Hz, 2H), 3.83-3.69 (m, 2H), 2.40-2.28 (m, 1H), 2.09-2.01 (m, 1H), 1.84(p, J=6.7 Hz, 2H), 1.50-1.44 (m, 5H), 1.40-1.24 (m, 14H), 0.89 (t, J=7.0Hz, 2H); MS (ESI+): Calcd for C₂₆H₃₇F₃N₃O₅ [M+H]: 528.3, Found: 528.4.

(2S,3S)-3-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonitrile

Synthesized by General Procedure DD. 31% yield, colorless oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.27 (d, J=2.2 Hz, 1H), 8.18 (dd, J=8.7, 2.2Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 4.94-4.91 (m, 1H), 4.76-4.72 (m, 1H),4.12 (t, 6.4 Hz, 2H), 3.91-3.82 (m, 2H), 2.42-2.31 (m, 2H), 2.18-2.10(m, 1H), 1.89-1.81 (m, 2H), 1.53-1.45 (m, 2H), 1.40-1.24 (m, 8H),0.92-0.86 (m, 3H).

Example 113:(2S,3S)—N,3-dihydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide(Compound 6)

Synthesized by General Procedure EE. 44% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 8.30-8.24 (m, 1H), 8.16 (ddd, J=8.6, 4.0, 2.4 Hz,1H), 7.09-7.02 (m, 1H), 4.78-4.66 (m, 1H), 4.51-4.48 (m, 1H), 4.14-4.06(m, 2H), 3.39-3.25 (m, 1H), 2.96 (s, 2H), 2.27-2.17 (m, 1H), 1.96 (ddt,J=16.0, 7.6, 3.5 Hz, 1H), 1.83 (dtt, J=12.4, 6.3, 3.0 Hz, 2H), 1.48 (p,J=7.2 Hz, 2H), 1.40-1.24 (m, 10H), 0.89 (td, J=7.1, 1.3 Hz, 3H); MS(ESI+): Calc'd for C₂₂H₃₁F₃N₅O₄ [M+H]: 486.2, Found: 486.4.

tert-butyl(S)-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxylate

Synthesized by General Procedures CC. 76% yield, yellow oil; ¹H NMR (400MHz, CDCl₃) δ 8.28 (s, 1H), 8.185 (d, J=8.7 Hz, 1H), 7.07 (d, J=8.6 Hz,1H), 5.26-4.85 (m, 1H), 4.11 (t, J=6.2 Hz, 2H), 3.76-3.64 (m, 1H),3.62-3.44 (m, 1H), 2.48-2.31 (m, 1H), 2.21-2.10 (m, 2H), 2.07-1.96 (m,1H), 1.84 (p, J=6.7 Hz, 2H), 1.53-1.43 (m, 5H), 1.39-1.22 (m, 14H), 0.88(t, J=6.5 Hz, 3H);

¹H NMR (101 MHz, CDCl₃) δ 180.9, 167.4, 159.4, 153.6, 132.5, 126.5,123.6 (q, 1J_(CF)=275.9 Hz), 119.8, 118.6, 113.0, 80.6, 69.2, 10 53.9,46.5, 32.5, 31.9, 31.6, 29.3, 29.0, 28.3, 25.9, 24.5, 23.8, 22.8, 14.2.¹⁹F NMR (376 MHz, CDCl₃) δ −62.8 (d, J=15.1 Hz, 3F); HRMS (ESI+): Calcdfor C₂₆H₃₆F₃N₃O₄Na[M+Na]: 534.2555, Found: 534.2506.

(S)-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonitrile

Synthesized by General Procedure DD. 68% yield, colorless oil; ¹H NMR(600 MHz, Chloroform-d) δ 8.28 (d, J=2.1 Hz, 1H), 8.20 (dd, J=8.7, 2.2Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 5.02 (dd, J=8.1, 3.9 Hz, 1H), 4.12 (t,J=6.4 Hz, 2H), 3.82-3.75 (m, 1H), 3.65-3.57 (m, 1H), 2.50-2.41 (m, 1H),2.39-2.31 (m, 1H), 2.27-2.09 (m, 2H), 1.89-1.81 (m, 2H), 1.53-1.45 (m,2H), 1.42-1.22 (m, 9H), 0.89 (d, J=7.0 Hz, 3H).

Example 114:(S)—N-hydroxy-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide(Compound 97)

Synthesized by General Procedure EE. 37% yield, white solid; ¹H NMR (600MHz, Chloroform-d) δ 8.26 (d, J=2.1 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz,1H), 7.05 (d, J=8.7 Hz, 1H), 5.29 (d, J=8.1 Hz, 1H), 4.74 (s, 2H), 4.10(t, J=6.4 Hz, 2H), 3.68-3.62 (m, 1H), 3.51 (q, J=8.1 Hz, 1H), 2.43-2.33(m, 1H), 2.32-2.21 (m, 2H), 2.19-2.10 (m, 1H), 1.88-1.80 (m, 2H),1.53-1.44 (m, 2H), 1.40-1.22 (m, 10H), 0.88 (t, J=7.0 Hz, 4H); MS(ESI+): Calc'd for C₂₂H₃₁F₃N₅O₃ [M+H]: 470.2, Found: 470.4.

Inhibition of Sphingosine Kinase Type 2

Four C57Bl/6 mice were dosed by oral gavage with 20 mg/kg of Compound 6(Example 113). Blood was drawn immediately, at 2h, 6, and 24 h afteradministration, whole prepared for analysis, and the amount ofsphingosine 1-phosphate (S1P) was quantified by LC-MS-MS, as shown inFIG. 1A. The results show a rise in S1P, which rise is indicative ofinhibition of sphingosine kinase type 2 (SphK2).

The amount of Compound 6 (red) and its reduced form Compound 6A (theactive drug, blue) were detected by LC-MS-MS in the same blood samples.FIG. 1B shows that pro-drug Compound 6 gave rise to Compound 6A over theperiod of measurement.

Where descriptions of various embodiments use the term “comprising,”those skilled in the art would understand that in some specificinstances, an embodiment can be alternatively described using language“consisting essentially of” or “consisting of.”

While the invention has been described and exemplified in sufficientdetail for those skilled in this art to make and use it, variousalternatives, modifications, and improvements will be apparent to thoseskilled in the art without departing from the spirit and scope of theclaims.

All patents and publications referred to herein are incorporated byreference herein to the same extent as if each individual publicationwas specifically and individually indicated to be incorporated byreference in its entirety.

1. A method of treating a disease in a patient suffering therefrom,wherein the disease is selected from a neoplastic disease, a diseaseinvolving excess vascular growth, an allergic disease, an inflammatorydisease of the eye, an inflammatory disease of the kidney, a fibroticdisease, an autoimmune disease, acute lung injury, sepsis, capillaryleak syndrome, pneumonia, ischemia reperfusion injury, acute kidneyinjury, age-related macular degeneration, diabetic retinopathy,atherosclerosis, and pulmonary arterial hypertension, the methodcomprising administering to the patient an effective amount of acompound according to formula (I)

wherein X is phenyl, indolyl, or naphthyl; R¹ and R² are independentlyselected from the group consisting of H, OH, —(C₁-C₆)alkyl-OH, halo,NH₂, NOH, NHOH, and CN; or R¹ and R², if bound to adjacent carbon atoms,in combination with the existing carbon-carbon bond represent a doublebond between the adjacent carbon atoms; R³ and R⁴ are independentlyselected from the group consisting of H, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₁-C₆)haloalkyl, CN, and halo; m=0 or 1; W is CH₂, Oor, NH; V is selected from the group consisting of H, (C₁-C₁₀)alkyl,(C₂-C₁₂)alkenyl, —(C₁-C₁₀)alkyl-(C₆-C₁₀)aryl,—(C₂-C₁₂)alkenyl-(C₆-C₁₀)aryl,—(C₁-C₁₀)alkyl-(C₆-C₁₀)aryl-(C₁-C₁₀)alkyl,—(C₁-C₁₀)alkyl-(C₃-C₈)cycloalkyl, —(C₁-C₁₀)alkyl-heterocyclyl containingfrom 1 to 3 ring heteroatoms selected from N, O, and S; wherein any arylis optionally fused to (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, or heterocyclylcontaining from 1 to 3 ring heteroatoms selected from N, O, and Swherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, or aryl isoptionally substituted by 1-4 substituents independently selected fromthe group consisting of F, Cl, Br, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl, and CN; Y¹, Y², and Y³are independently selected from the group consisting of C, N, NH, O, andS; or a pharmaceutically acceptable salt thereof.
 2. The methodaccording to claim 1, wherein m is 1; and Y¹ is N; Y² is N and Y³ is O;or Y² is O and Y³ is N.
 3. The method according to claim 2, wherein R¹and R² are independently selected from the group consisting of H, OH,CH₂OH, F, and Cl.
 4. The method according to claim 3, wherein X isphenyl; and one of R³ and R⁴ is —CF₃.
 5. The method according to claim1, where the compound is according to formula (II):

wherein: R¹ and R² are H, or when m=1, one of R¹ and R² can be OH; R³and R⁴ are each independently H, (C₁-C₄)alkyl, cyclopropyl,(C₁-C₂)fluoroalkyl, cyano, or halo; m=0 or 1; each of Y¹, Y², and Y³ isindependently selected from the group consisting of C, N, NH, O, and S;X is a phenyl, naphthyl, or indolyl; W is O or CH₂; V is (C₅-C₁₀)alkyl;or a pharmaceutically acceptable salt thereof.
 6. The method accordingto claim 5, wherein the ring comprising Y¹, Y², and Y³ is an oxadiazolering.
 7. The method according to claim 5, wherein R¹ and R² are bothhydrogen.
 8. The method according to claim 5 wherein X is phenyl.
 9. Themethod according to claim 8, wherein m is 1 and R² is OH.
 10. The methodaccording to claim 5 wherein X is naphthyl.
 11. The method according toclaim 5 wherein X is indolyl.
 12. The method according to claim 1wherein R³ is trifluoromethyl.
 13. The method according to claim 1wherein R⁴ is hydrogen.
 14. The method according to claim 1, wherein thecompound or a pharmaceutically acceptable sale thereof is one selectedfrom the following table:

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97


15. The method according to claim 1, wherein the disease is a fibroticdisease.
 16. The method according to claim 15, wherein the fibroticdisease is pulmonary fibrosis, renal fibrosis, cardiac fibrosis, orhepatic fibrosis.
 17. The method according to claim 16, wherein thefibrotic disease is renal fibrosis.
 18. A method of inhibiting asphingosine kinase, comprising contacting the sphingosine kinase with aneffective amount of a compound according to formula (I)

wherein X is phenyl, indolyl, or naphthyl; R¹ and R² are independentlyselected from the group consisting of H, OH, —(C₁-C₆)alkyl-OH, halo,NH₂, NOH, NHOH, and CN; or R¹ and R², if bound to adjacent carbon atoms,in combination with the existing carbon-carbon bond represent a doublebond between the adjacent carbon atoms; R³ and R⁴ are independentlyselected from the group consisting of H, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₁-C₆)haloalkyl, CN, and halo; m=0 or 1; W is CH₂, Oor, NH; V is selected from the group consisting of H, (C₁-C₁₀)alkyl,(C₂-C₁₂)alkenyl, —(C₁-C₁₀)alkyl-(C₆-C₁₀)aryl,—(C₂-C₁₂)alkenyl-(C₆-C₁₀)aryl,—(C₁-C₁₀)alkyl-(C₆-C₁₀)aryl-(C₁-C₁₀)alkyl,—(C₁-C₁₀)alkyl-(C₃-C₈)cycloalkyl, —(C₁-C₁₀)alkyl-heterocyclyl containingfrom 1 to 3 ring heteroatoms selected from N, O, and S; wherein any arylis optionally fused to (C₆-C₁₀)aryl, (C₃-C₈)cycloalkyl, or heterocyclylcontaining from 1 to 3 ring heteroatoms selected from N, O, and Swherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, or aryl isoptionally substituted by 1-4 substituents independently selected fromthe group consisting of F, Cl, Br, (C₁-C₆)alkyl, —O—(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₆-C₁₀)aryl, and CN; Y¹, Y², and Y³are independently selected from the group consisting of C, N, NH, O, andS; or a pharmaceutically acceptable salt thereof.
 19. The methodaccording to claim 18, wherein the sphingosine kinase is sphingosinekinase type 1 or sphingosine kinase type 2, or both.
 20. The methodaccording to claim 19, further comprising selectively inhibitingsphingosine kinase type 2 relative to sphingosine kinase type 1.